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immunotherapy: mechanism, design, recent

Cite this: DOI: 10.1039/d2cs00437b
advances, and clinical translation
Haonan Li, †a Qiang Luo,†a Hu Zhang, c
Xuelei Ma,a Zhongwei Gu, a

Qiyong Gong*ab and Kui Luo *ab

Cancer radio-immunotherapy, integrating external/internal radiation therapy with immuno-oncology treatments,

Received 21st July 2022
DOI: 10.1039/d2cs00437b
rsc.li/chem-soc-rev
emerges in the current management of cancer. A growing number of pre-clinical studies and clinical trials have
recently validated the synergistic antitumor effect of radio-immunotherapy, far beyond the ‘‘abscopal effect’’, but
it suffers from a low response rate and toxicity issues. To this end, nanomedicines with an optimized design
have been introduced to improve cancer radio-immunotherapy. Specifically, these nanomedicines are elegantly
prepared by incorporating tumor antigens, immuno- or radio-regulators, or biomarker-specific imaging agents
into the corresponding optimized nanoformulations. Moreover, they contribute to inducing various biological
effects, such as generating in situ vaccination, promoting immunogenic cell death, overcoming radiation
resistance, reversing immunosuppression, as well as pre-stratifying patients and assessing therapeutic response
or therapy-induced toxicity. Overall, this review aims to provide a comprehensive landscape of nanomedicine-
assisted radio-immunotherapy. The underlying working principles and the corresponding design strategies for
these nanomedicines are elaborated by following the concept of ‘‘from bench to clinic’’. Their state-of-the-art
applications, concerns over their clinical translation, along with perspectives are covered.

a
Department of Radiology, Department of Biotherapy, Huaxi MR Research Center 1. Introduction
(HMRRC), Cancer Center, Frontiers Science Center for Disease-Related Molecular
Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan In recent years, cancer immunotherapy, harnessing the innate
University, No. 37 Guoxue Alley, Chengdu 610041, China. or adaptive host immune systems to combat cancer, has
E-mail: qiyonggong@hmrrc.org.cn, luokui@scu.edu.cn enjoyed a flourishing growth rate. Generally, it is divided into
b
Functional and Molecular Imaging Key Laboratory of Sichuan Province and two major antineoplastic approaches: active cancer vaccines for
Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu
prophylactic or therapeutic use and passive immuno-oncology
610041, China
c
Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA 91711, USA treatments.1 Passive treatments include administration of
† These authors contributed equally. immune checkpoint inhibitors (ICIs) targeting programmed

Haonan Li received his M. M. Qiang Luo received his PhD degree

degree from Sichuan University in
2020 under the supervision of Prof.
Kui Luo and Prof. Qiyong Gong.
Currently, he is pursuing a PhD
degree under the guidance of Prof.
Kui Luo at the Huaxi MR Research
Center at West China Hospital,
Sichuan University. His research
interests focus on the smart
nanomedicine-aided cancer radio-
immunotherapy, theranostics, and
Haonan Li molecular imaging.
from Sichuan University in 2021.
He then joined the postdoctoral
position at West China Hospital,
Sichuan University, under the
guidance of Prof. Kui Luo and
Prof. Qiyong Gong. His research
focuses on nanomedicine-assisted
tumor therapy, radionuclide-based
cardiac interventional radio-
therapy, and the treatment of
immunotherapy-induced cardio-
Qiang Luo toxicity using intelligent nano-
medicine.

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death-1 (PD-1),2 programmed death ligand-1 (PD-L1) or cyto-
toxicity T-lymphocyte-associated protein 4 (CTLA-4),3,4 injection
of chimeric antigen receptor T-cell therapy (CAR T),5 bispecific
antibodies (bsAbs, e.g., blinatumomab),6 costimulatory recep-
tors (e.g., CD137, CD134, and toll-like receptor) agonists,7,8 and
interferons/immunocytokines (e.g., interleukin-12).9 However,
as indicated by increasing evidence, this cancer treatment
suffers from a low response rate on several types of solid
tumors, limited patient benefits, immune-related adverse
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events, and pseudoprogression.10,11
Inspired by enormous benefits achieved by combined ther-
apy, the combination of immunotherapy with radiation therapy
(RT), termed as radio-immunotherapy, has recently thrived as a
potent weapon fighting against cancer and a potential solution
Prof. Hu Zhang received his PhD
degree in Biochemical Engineering
from the Department of Bio-
chemical Engineering at University
College London (UK) in 2004. He is
currently an Adjunct Professor in
Bioprocessing at Keck Graduate
Institute (USA). Prof. Zhang has
published over 130 peer-viewed
papers. His research focuses on
applying emerging techniques to
biological processes and systems to
Hu Zhang produce valuable biological or
chemical products, as well as
smart nanomedicine for drug and
gene delivery.
Prof. Qiyong Gong is currently a
Full Professor of Clinical
Radiology at the West China
Hospital of Sichuan University,
Director of the Key Laboratory of
Functional and Molecular
Imaging of Sichuan Province,
and the President of West China
Xiamen Hospital of Sichuan
University. Prof. Gong has
published more than 600 peer-
viewed papers, with an h-index
Qiyong Gong of 91, and he is the 2018–19,
2022 Highly Cited Researcher by
Web of Science Group of the Clarivate Analytics. The main research
in his lab focuses on magnetic resonance imaging of psychiatric
disorders and brain tumors, as well as functional nanomedicines
for molecular imaging and cancer therapy.
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to the above concerns.12–14 Briefly, RT and immunotherapy
share a solid biological basis for their synergistic antitumor
effect. RT, consisting of external beam irradiation (X-rays, g-
rays, protons, or carbon ions) and internal radioisotope-
mediated brachytherapy,15 is a prevalent cancer treatment
method as nearly 50% of cancer patients have received RT.16
For antitumor therapy, RT exhibits a local tumoricidal effect
and induces stromal, immunological, and vascular changes,
but it often fails to treat metastases. In this context, systemic
immunotherapy is an excellent addition to RT to achieve a
whole-body anti-primary-tumor and anti-metastasis therapy. In
addition, RT can evoke various immunogenic responses, parti-
cularly immunogenic cell death (ICD) and the ‘‘abscopal
effect’’.17 Thus, RT may act as a response enhancer for
Prof. Zhongwei Gu is a Professor
at the West China Hospital of
Sichuan University. Prof. Gu has
been appointed as a Chief
Scientist of the National Basic
Research Program of China (the
973 Program) for three five-year
periods since 1999. He has
awarded numerous awards,
including the Fellow of the
International Union of Societies
for Biomaterials Science and
Zhongwei Gu Engineering (FBSE) and the
Distinguished Visiting Fellow-
ship Award of the Royal Academy of Engineering. He has
published over 300 peer-reviewed scientific manuscripts and held
more than 30 issued patents. His research activities focus on
nanobiomaterials, biomimetic delivery systems, and tissue
engineering.
Prof. Kui Luo received his PhD
degree in Biomedical Engineering
(2009) from Sichuan University
under the supervision of Prof.
Zhongwei Gu. From 2009 to 2011,
he carried out postdoctoral work on
polymeric nanomedicines at the
University of Utah, USA. Dr Luo
was promoted to an Associate
Professor in 2012 and a Full
Professor in 2013 in Sichuan
University. From 2016, he is a Full
Kui Luo Professor and PI in West China
Hospital, Sichuan University,
China. He has authored over 140 peer-reviewed publications with an
h-index of 43. His research interests include nanomedicines, polymers-
based imaging agents and drug/gene delivery systems.
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immuno-oncology treatments in a systemic immune-associated
manner or a local therapy-focused manner. Specifically, multi-
ple effects induced by RT, such as inducing in situ cancer
vaccinations for tumor eradication and immune memory
maintenance,18 overcoming the barrier of the dense tumor
matrix and normalizing tumor vascular for easy access of ICIs
and CAR T cells to the tumor tissue,19 or activating the cGMP-
AMP synthase-stimulator of interferon gene (cGAS-STING) path-
way for the recruitment of pro-inflammatory chemokines,20
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have been found to be associated with an enhancement in
the immune response. Furthermore, RT at a low dose has been
demonstrated to help in normalizing the tumor vasculature,
evoking the systemic immune response, and reprogramming
the tumor stroma.21 However, high-dose RT is capable of
causing severe blood vessel damage, overcoming a large tumor
burden, and converting ‘‘cold’’ tumors to ‘‘hot’’ ones that are
much more sensitive to immunotherapy.22,23 For example,
brachytherapy at a high dose of 10 Gy was found to convert

Fig. 1 Scheme for nanomedicine-assisted cancer radio-immunotherapy. Optimized strategies in designing nanomedicines include surface modification
for eliciting immune response, structure modification for RT-responsive drug release, as well as incorporating chemical moieties for prolonging
circulation, enhancing cell uptake, and promoting excretion after the treatment. Nanomedicines have played a critical role in cancer radio-
immunotherapy: (i) pre-stratification at a stimulation dose for selecting patients for radio-immunotherapy or therapeutic response assessment for
adjusting treatment plans. (ii) Improving cancer vaccination through (a) nanomedicine-aided capture and presentation of RT-induced released antigens;
(b) RT-treated tumor cell membranes as a component of personalized cancer nanovaccines; (c) RT-induced priming of the tumor microenvironment
(TME) for exogenous cancer nanovaccines. (iii) Prompting immunogenic cell death through imposing endoplasmic reticulum stress and releasing
immunological regulating agents. (iv) Mitigating therapy resistance through addressing biological or pathological barriers via active targeting and
extracellular matrix/vascular normalization, as well as reversing immunosuppression and radioresistance. (v) Reducing radio-immunotherapy-induced
toxicities through accelerating blood clearance of antibodies, pre-protecting immunocytokines, and addressing radiation proctopathy.

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80% of ‘‘cold’’ prostate cancer cells into ‘‘intermediate’’ or
‘‘hot’’ immune subtypes in 24 prostate cancer patients.24 Mean-
while, several studies have implied that immunotherapy can
aid in prompting the ‘‘abscopal effect’’ induced by RT.25,26
Recent years have witnessed encouraging results from clinical
trials of radio-immunotherapy; however, cancer radio-
immunotherapy is hindered by three critical issues. First, the
aggregate antitumor potency is still inadequate to treat a sum of
indications, for example, dormant lesions in cancer patients and
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immunosuppressive tumor types.27 Second, innate or adaptive
resistance to radio- and/or immuno-therapy, as well as these
therapies-related adverse effects, has been reported.28,29 Third,
there is a lack of valid criteria to help in guiding and assessing
this radio-immunotherapy. For example, imaging manifestations,
like hyperprogression and pseudoprogression, could display a false
signal, leading to a significant delay in the treatment plan.30
To address the above issues, nanomedicines have garnered
increasing interest for cancer radio-immunotherapy due to their
improved pharmacokinetics and incredible auxiliary functions
(Fig. 1). Unique physicochemical properties and functional mod-
ifications endow these nanomedicines with the ability to overcome
the obstacles encountered by conventional chemo- or immuno-
therapeutic drugs, such as a low therapeutic drug concentration in
the region of interest, non-specific distribution in healthy organs or
tissues, and a rapid excretion rate.31–34 Effectiveness and a low-toxic
profile of liposome- or albumin-based nanomedicines have been
demonstrated in routine cancer treatment.35–37 A myriad of nano-
medicines have been explored for radio-immunotherapy. Basically,
they are designed to promote the interaction between RT and
antitumor immunity. For example, in one aspect, nano-
radiosensitizers augment local radiation deposition and improve
radioresistance, resulting in increased ICD and in situ
vaccination.38,39 In other aspects, nanocarriers with/without intrin-
sic bioactive properties have been applied to deliver therapeutic/
diagnostic radionuclides, tumor antigens, ICIs, and immunomo-
dulators to provoke strong, durable antitumor immunity, address
immunosuppression, and realize imaging-aided therapy.40,41
Besides, incorporation of nanomedicines into adoptive cells or
CAR T cells to deliver ICIs represents a clinical translational path
for radio-immunotherapy.42 Encouragingly, nanomedicines have
been applied in routine clinical practices and more in clinical trials
or pre-clinical studies for radio-, immuno-, or combinational radio-
immuno-therapy.
Overall, this review provides a comprehensive coverage of
nanomedicine-assisted cancer radio-immunotherapy, includ-
ing design strategies and synergetic antitumor mechanisms
of nanomedicines for radio-immunotherapy. Their recent
applications in solid tumors and considerations over their
clinical translation have also been elaborated.
2. Cancer immunotherapy embraces
radiotherapy
After years of rapid expansion of cancer immunotherapy,
accumulative evidence indicates that the combinational
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therapies, particularly the integration of renascent immu-
notherapy with radiotherapy, have great potential to replace
mono-immunotherapy and become the mainstream workforce
in immuno-oncology-based treatments.43,44
Non-irradiated remote tumor recession on patients who are
subjected to RT is the clinical basis to develop cancer radio-
immunotherapy. This phenomenon, termed as the ‘‘abscopal
effect’’, is well-known, but it is a low incidence event in clinical
practice, mainly due to insufficient antitumor immune
response elicited by RT and an immunosuppressive TME.45 In
a recent clinical trial, about 29% of 168 patients with advanced
tumors receiving anti-PD-1 and RT showed the ‘‘abscopal
effect’’.46 The underlying mechanism of this effect is complex
and remains to be understood. Immunomodulatory signals or
agents including DNA damage-induced inflammatory signals,
released tumor neoantigens, and dendritic cell maturation
stimulators have been found to contribute to the effect,47,48
but the effect was not seen in immunodeficient athymic mice
that received RT.49 Thus, this effect confirms the immunomo-
dulatory properties of RT and multiple biological processes are
involved in the effect.
2.1 Biological synergistic basis of cancer radio-
immunotherapy
The primary biological synergistic basis of cancer radio-
immunotherapy is shown in Fig. 2, which includes the immu-
nomodulating effect of RT and the radio-sensitization effect of
immunotherapy.
(i) RT induces ICD. RT directly triggers the release of
tumor antigens and damage-associated molecular patterns
(DAMPs) including calreticulin (CRT), adenosine 5 0 -triphos-
phate (ATP), and high mobility group protein B1 (HMGB1).50
It indirectly increases the level of reactive oxygen species (ROS)
and endoplasmic reticulum (ER) stress, leading to ICD.17
(ii) RT induces vaccination. As a means of deeply-
penetrated, damage-generating stimulation, RT significantly
enriches the variety and amount of tumor antigens including
tumor-associated antigens (TAAs) and tumor-specific antigens
(TSAs) and subsequently induces their release, thereby improv-
ing tumoral antigenicity and promoting in situ vaccination.
Upregulated expression and enhanced presentation of TAAs
after RT result in potent cancer vaccination, and TSAs origi-
nated from RT-induced or somatic nonsynonymous mutations
may not easily develop immune tolerance and can be further
utilized to develop neoantigen-based peptide cancer vaccines.51
Specifically, four gene mutations (Adgrf5, Cand1, Dhx58, and
Raet1e) upregulated by RT (8 Gy  3 fractions) and their
encoded immunogenic neoepitopes in 4T1 cells were recently
identified.52 In addition, it was reported that immunogenic
mutation in a gene, KPNA2, upon radiation-induced exposure
occurred in a lung cancer patient after surgical removal of two
brain metastases.53 RT has also been found to increase the
amount of major histocompatibility complex I in the tumor cell
membrane, facilitating recognition of effector T cells towards
tumor neoantigens.54 Moreover, RT-induced tumor debris
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Fig. 2 Illustration of the biological basis of cancer radio-immunotherapy. (a) RT elicits immunogenic cell death (ICD). RT increases the reactive oxygen
species (ROS) level and endoplasmic reticulum (ER) stress, as well as releases damage-associated molecular patterns to activate dendritic cells (DCs). The
release of various chemokines from DCs helps induction and recruitment of immune cells. (b) RT induces cancer vaccination. RT helps releasing tumor
antigens and upregulating major histocompatibility complex I (MHC-I), contributing to enhancing the antitumor effect of the antigen-specific
cytotoxicity T cells. (c) RT activates the cGAS-STING pathway to generate type I interferons, which can enhance the antitumor immunity and increase
the PD-L1 expression that are favorable for anti-PD-L1-based immunotherapy. (d) RT primes the tumor microenvironment (TME), allowing easy access of
immunotherapeutic agents (ICIs, CAR T, or bsAbs) to tumor sites and establishing favorable microenvironmental conditions for immunotherapy. ECM,
extracellular matrix; CAF, cancer-associated fibroblast; TAM, tumor-associated macrophage.

releases DAMPs and proinflammatory cytokines, resulting in
the activation of antigen-presenting cells (APCs).55
(iii) RT activates the cGAS-STING signaling axis. RT can
induce breakage of double-stranded DNA in tumor cells. The
broken DNA is sensed by cyclic GMP-AMP synthase (cGAS),
resulting in the activation of the stimulator of interferon gene
(STING), an innate immune sensor that can induce the genera-
tion of type I interferons and pro-inflammatory factors to
activate DCs.56 These DCs acquire the expression of the C–C
chemokine receptor 7 and they migrate to the tumor-draining
lymph nodes for tumor neoantigen presentation.26,57 Conver-
sely, another report revealed that STING after RT exerted an
immunosuppressive effect by inducing an influx of CCR2+M-
MDSCs.58
(iv) RT mediates priming of the TME as a neoadjuvant to
immunotherapy. RT has been found to help in reducing the
tumor burden, loosening the dense tumor matrix, normalizing
tumor vascular structures, and inducing an inflammatory TME.
This TME priming effect allows effective infiltration of high-
molecule-weight ICIs, large-size artificially modified cells, and
effector T cells, contributing to an immunotherapy-friendly
immune phenotype in the TME.59,60 Specifically, RT helps
increasing pattern recognition receptors and immune check-
points on tumor cells and thereby improves their sensitivity to
immunotherapy.61 Furthermore, markedly increased infiltra-
tion of eosinophils after RT treatment has been recently iden-
tified to improve the recruitment and anti-tumor response of
CD8+ T cells.62 To note, it has been unveiled that RT induces
pyroptosis, leading to an enhanced antitumor immunity in a
Caspase 9/Caspase 3/GSAME-mediated manner.63 Another
recent study has indicated that pre-existing inflammatory T
cells that survived after RT treatment could mediate the

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Table 1 Selected clinical trials for the combinational cancer radio-immunotherapy

Combinational Trial registration Enroll-

strategies no. Phase Status Indications ment Arms description Treatment outcome
RT + immune checkpoint inhibitor (ICI)
SBRT + durvalumab NCT02311361 I/II Completed Unresectable 65a Four cohorts: durvalumab +Acceptable safety profile;
(aPD-L1) or tremeli- (REF72) pancreatic 8 Gy  1 f (A1) or 5 Gy  modest treatment benefits:
mumab (aCTLA-4) cancer 5 f (A2), durvalumab + tre-
median PFS (1.7 vs. 2.5 vs.
melimumab + 8 Gy  1 f (B1)
0.9 vs. 2.3 months) and OS
or 5 Gy  5 f (B2) (3.3 vs. 9 vs. 2.1 vs. 4.2
months) in the cohorts A1,
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A2, B1, and B2, respectively

SBRT + pem- NCT02492568 II Completed Non-small 92a Two arms: pembrolizumab Similar toxicity profile;
brolizumab (aPD-1) (REF73) cell lung can- (A); SBRT (8 Gy  3 f) + clinical benefits: ORR (18%
cer (NSCLC) pembrolizumab (B) vs. 36%, p = 0.07), median
PFS (1.9 vs. 6.6 months, p =
0.19), and median OS (7.6
vs. 15.9 months, p = 0.16)
in the arm A and B,
respectively
EBRT + vaginal bra- NCT04214067 III Recruiting Stage I–II 168b Two arms: brachytherapy + Not available
chytherapy + endometrial EBRT; EBRT + brachyther-
pembrolizumab cancer apy + pembrolizumab
RT + chimeric antigen receptor T (CAR T) cells
Yttrium-90 micro- NCT02416466 I Completed Liver 8a One arm: anti-CEA CAR T No grade 4/5 toxicity
spheres + anti-CEA (REF74) metastases (three hepatic artery infu- events; clinical benefits:
CAR T sions) + Yttrium-90 median OS (6.9 months)
microspheres
RT + CAR T NCT04790747 I/II Recruiting Hematologi- 50b One arm: sequential RT + Not available
cal intravenous infusion of
malignancies CAR T
RT + bispecific antibody (bsAb)
131
I + omburtamab NCT01099644 I Active, not Peritoneal 54a One arm: intraperitoneal No dose-dependent toxi-
(REF75) recruiting cancer injection of 131I-8H9 cities; transient adverse
(omburtamab) effect; phase II activity was
established at 2.96 GBq
m2
Anti-CEA  anti- NCT01221675 I/II Completed CEA- 18a Two arms: optimization Absorbed doses predicted
HSG TF2 bsMAb + (REF76) expressing study and escalating activ- from pre-therapeutic ima-
IMP-288-Luteium + SCLC or ity phase I/II study ging session for therapy
IMP-288-Indium NSCLC session; a shorter pre-
targeting delay (24 h) and
the highest TF2 molar dose
were the best parameters
RT + cancer vaccine
EBRT + sipuleucel-T NCT01807065 II Completed Castrate- 51a Two arms: sipuleucel-T (A); Both arms were well-
(REF77) resistant EBRT + sequential tolerated; median PFS (2.46
prostate sipuleucel-T (B). vs. 3.65 months, p = 0.06)
cancer in the Arm A and B
Radium-233 + NCT02463799 II Completed Prostate 36a Two arms: radium-233 + No synergistic toxicity;
sipuleucel-T (REF78) cancer sipuleucel T (A); sipuleucel- median PFS (10.7 vs. 3.1
T (B). months, p = 0.02), PSA
response (33% vs. 0%, p =
0.04), and AlkPhos
response (60% vs. 7%, p =
0.01) in the arm A and B,
respectively
153
Sm-EDTMP + NCT00450619 II Completed Prostate 44a Two arms: 153Sm-EDTMP Both arms have similar
vaccine (REF79) cancer radiation (A); 153Sm- toxicity; median PFS (1.7
EDTMP + recombinant vs. 3.7 months, p = 0.034)
fowlpox- and vaccina- and a 430% PSA decline (0
TRICOM vaccine + sar- vs. 19%, p = 0.073) in the
gramostim (B). arm A and B, respectively
RT + autologous dendritic cells (DCs)
EBRT + autologous NCT01347034 II Completed Soft tissue 20a Two arms: EBRT alone; One in fourteen had ser-
DCs sarcoma EBRT + autologous DCs ious adverse events in the
(i.t.). treatment group with EBRT
+ DC injection; therapeutic
outcome is not given.
RT + DC immuniza- NCT03548571 II/III Recruiting Glioblastoma 60b Two arms: DC immuniza- Not available
tion + tion (i.d.) + subsequent RT
temozolomide (2 Gy  30 f) and temozo-
lomide; RT (2 Gy  30 f)
and temozolomide

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Table 1 (continued)

Combinational Trial registration Enroll-

strategies no. Phase Status Indications ment Arms description Treatment outcome
RT + costimulatory receptor agonist
RT + GLA-SE (TLR4 NCT02180698 I Completed Metastatic 16a One arm: glucopyranosyl Grade 1 or 2 toxicity; local
agonist) (REF80) sarcoma lipid A-stable-emulsion tumor control (14/14), and
(GLA-SE) + RT 1 CR, 1 PR, and 11 SD on
156 days post-trial
RT + imiquimod NCT01421017 I/II Completed Breast cancer 31a Three arms: RT + imiqui- All but one adverse event
(TLR7 agonist) (REF81) with chest mod; RT + cyclopho- was grade 1 or 2; abscopal
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wall recur- sphamide; RT + response was generated in

rence or skin cyclophosphamide + 3/9 cases
metastases imiquimod
RT + interferon/immunocytokine
SBRT + L19-IL2 NCT02086721 I Completed Oligometa- 6a One arm: SBRT + sub- Recommended dose in
(REF82) static solid sequent L19-IL2 (i.v.) phase II is 15 million
tumors international Units
SABR + Darleukin NCT03705403 II Recruiting Stage IV 126b Two arms: standard of care Not available
(L19-IL2) (REF83,84) NSCLC SABR and/or RT; SABR and/
or RT + L19-IL2
Abbreviations: SBRT, stereotactic body radiation therapy; PFS, progression free survival; OS, overall survival; ORR, overall response rate; EBRT,
external beam radiation therapy; CEA, carcinoembryonic antigen; SCLC, small cell lung cancer; HSG, histamine–succinyl–glycine; 153Sm-EDTMP,
samarium 153 lexidronam pentasodium; TLR, toll-like receptor; CR, complete response; PR, partial response; SD, stable disease; SABR, stereotactic
ablative body radiotherapy. a Represents the actual participants. b Indicates the estimated number (All data but therapeutic outcome were
accessed from ClinicalTrials.gov).

activation of local antitumor immune response and exert a
highly potent therapeutic effect in comparison with freshly
infiltrating T cells.64 Moreover, it was reported that in an
orthotopic glioblastoma mice model, long-term intravital
microscopy fluorescence images confirmed that RT aided in
rapid extravasation of CAR T cells from vasculature and their
expansion in the TME.65
(v) Immunotherapy curbs non-irradiated distant tumors.
One significant unique advantage of radio-immunotherapy is
that two individual therapies can complement in controlling
primary tumors and distant metastases. Immunotherapy can
be an excellent addition to RT in advanced cancers since multi-
site radiation cannot completely cover distant tumors in
advanced cancers.66
(vi) Immunotherapy induces TME priming as a neoadju-
vant to RT. Sufficient intratumoral infiltration of immune
effector cells or reduction of immunosuppressive cells induced
by immunotherapy contributes to a supportive TME for sub-
sequent RT treatment. For example, in a study conducted on
two orthotopic head and neck cancer murine models, a murine
MOC2-bearing C57BL/6 model and a murine LY2-bearing
BALB/c model, targeting regulatory T cells by inhibiting STAT3
was found to improve the therapeutic efficacy of RT.67
Additionally, a recent study based on murine tumor models
and the cancer patient samples after treatment with RT and
anti-PD-L1 immunotherapy revealed that both treatments
shared a similar adaptive immune response by eliminating
tumor-promoting erythroid progenitor cells (Ter cells), which
secreted artemin to promote tumor growth.68 In summary,
their synergistic effects on alleviating early-stage/late-stage
small/large tumor burdens, curbing local foci/distant metas-
tases, activating the antitumor immunity at dormant tumor
sites, and preventing tumor recurrence can be harnessed for
combating advanced cancers.69
2.2 Current landscape of cancer radio-immunotherapy
Recent years have witnessed the successful development of
cancer radio-immunotherapy. Hundreds of clinical trials on
this topic have been registered, and their recent progress has
been summarized elsewhere.70,71 Various RT methods, such as
external beam radiation therapy or brachytherapy with hypo- or
hyper-fractionation at a high- or low-radiation dose using
different radiation sources, have been combined with different
immuno-oncology treatments including ICIs, CAR T, bsAbs, or
cytokines via different modes of administration (i.v., s.c., i.p.,
and i.d.) sequentially or concurrently. The safety and efficacy of
these combination treatments have been evaluated, and their
indications include but are not limited to non-small cell lung
cancer, glioblastoma, pancreatic cancer, soft tissue sarcoma,
and prostate cancer. Herein, a few representative clinical trials
are listed in Table 1.
Beyond these selected clinical trials, analysis results of two
large-datasets provide a current summary of the therapeutic
outcomes in the combinational treatment of immunotherapy
and RT. An analysis of the National Cancer Database reveals
that the addition of immunotherapy to RT contributes to an
improved overall survival time (OS) in melanoma brain metas-
tases according to the data from 1104 patients. 192 patients
received both RT and immunotherapy with a median OS of 11.1
months, while the rest were treated with RT alone with a
median OS of 6.2 months.85 However, a retrospective analysis
of patients with metastatic NSCLC, among which 6383 received
RT plus immunotherapy and 170 479 received hypofractionated
RT alone, reveals no difference in the overall survival time
between two groups.86 Thus, this combined therapy displayed
encouraging therapeutic outcomes for a few cancer types, but it
is not effective against other indications. Additionally, several
issues, including ambiguity between pseudoprogression and

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tumor progression, the off-target effect of immune-adjuvants
and radio-enhancers, and therapeutic resistance, contribute
to under-expected therapeutic efficacies and severe systemic
toxicities.
3. Nanomedicines aid in cancer radio-
immunotherapy
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four categories: immunomodulators, radiosensitizers, regula-
tors for improving both therapies, and probes for diagnosis,
therapeutic response evaluation, or imaging-assisted treat-
ments. In this combinational treatment, nanomedicines may
play multiple roles through incorporation of different func-
tional groups (Fig. 3).
Nanomedicine-enabled immunomodulation. The nano-
medicine-mediated immunomodulation effect has been sum-
marized by Nam et al. and Irvine et al.87,88 The effect is

3.1 Basic mechanisms predominantly related to single or multiple phases of the

Overall, application of nanomedicines improves the safety and cancer immunity cycle, such as improving antigen presenta-
efficacy of cancer radio-immunotherapy. Potential roles of tion, restoring T cell function, and promoting cancer
nanomedicines in this combined therapy can be divided into vaccination.87,88

Fig. 3 Illustration of four major roles of nanomedicine in cancer radio-immunotherapy. (a) Nanomedicine-mediated immunomodulation. The role of
nanomedicines in improving immunotherapy includes: (i) acting as exogenous nanovaccines and antigen-capturing NPs; (ii) delivery of small-molecule
immunomodulatory agents; (iii) delivery of ICIs & cytokines; (iv) nano-modifiers for immune cells. (b) Nanomedicine-aided radiation sensitization through
increasing radiation-dose deposition and ROS generation, improving tumor oxygenation and exacerbating DNA damage, and decreasing GSH generation
and preventing DNA repair. (c) Nanomedicine-contributed assistance in improving both radiotherapy and immunotherapy through interfering with their
shared signaling pathways (e.g., cGAS-STING) and reducing therapy resistance. (d) Nanomedicine-participated imaging visualizes the tumoral
accumulation of nanomedicines and semi-quantifies specific biomarkers for radio-immunotherapy in pre-selecting patients for this combinational
treatment or assessing therapeutic response.

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In cancer radio-immunotherapy, there are four main speci-
fic immunomodulatory roles of nanomedicines. 1. They act as
cancer nanovaccines or antigen-capturing NPs. Briefly, exo-
somes or irradiated cell membranes of RT-treated tumor cells
are used as personalized cancer nanovaccines due to the
abundance of tumor neoantigens and DAMPs in them. The
use of antigen-capturing NPs can help in adsorbing and pre-
senting released antigens after RT, favoring DC activation
and enhancing antigen-specific T cell-mediated antitumor
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immune response.89,90 2. They deliver immunomodulatory
agents in the manner of physical encapsulation or chemical
conjugation.91–93 Agonists of STING and TLR, as well as inhi-
bitors of indoleamine-2,3-dioxygenase (IDO), have been incor-
porated into the nanoscale delivery system, contributing to
evading immune escape or potentiating ICI-based antitumor
immune response for RT.94,95 3. They deliver ICIs and cyto-
kines. Inefficient delivery and unpleasant systemic toxicity of
immuno-drugs hamper their clinical application, while nano-
technology may help in addressing these issues.96–98 For
instance, the result of a phase II clinical trial (NCT00396019)
with 86 participants indicates the administration of PEGylated
interferon Alfa-2b (PEG-Intron) to patients with plexiform neu-
rofibromas could significantly delay the onset of tumor pro-
gression in comparison to the placebo group.99 Additionally,
advanced nanotechnology-aided immunomodulatory nanome-
dicines have been developed, such as PD-L1 antagonist peptide-
decorated polymeric nanoparticles,100 a dendrimer–ICI
conjugate,101,102 and a cytokine or an antibody modified with
an inner stimuli-responsive mask agent.103,104 4. They can be
used to modify immune cells. Nanomedicines, mostly in the
form of nanogels, can be modified to attach to effector T cells
or macrophages via a backpacking approach to simultaneously
realize multiple functions, such as controlled release of IL15 to
selectively expand tumor-infiltrated T cells or IFN-g to maintain
proinflammatory M1 macrophages.105,106
Nanomedicine-aided radiation sensitization. One signifi-
cant advantage of nanomedicine-aided radiation sensitization
is the ability to maximize the immunogenic or therapeutic
effect of RT, but reduce the radiation dose to a safe level.107
There are three major means of realizing nanomedicine-
aided radiation sensitization: (i) amplifying local radiation
deposition and ROS generation by using high-Z nanomedi-
cines. Metal elements and their nano-derivatives with a high
atomic number and efficient nano-catalytic properties, particu-
larly in the form of metal–organic frameworks, including
hafnium oxide, gadolinium, gold, bismuth, platinum, polyox-
otungstate, titanium oxide, and tantalum, have been explored
for this radiation sensitization effect.38,108–110 For example,
hafnium oxide-containing nanoparticles (NBTXR3) have been
evaluated in 15 clinical trials and they have shown a promising
therapeutic effect. The working principle of this nanoparticle is
dose partitioning. An increased radiation dose is deposited
close to this high-Z radiosensitizer, resulting in improved
photoelectric interaction.111 In addition, the high-Z radiosensi-
tizer can contribute to non-oxygen-dependent ROS generation
by catalyzing a great amount of H2O2 in the TME. Furthermore,
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mitochondria- or endoplasmic reticulum-targeting nanomedi-
cines could contribute to highly-selective damage to tumor
cells;112–114 ii. Delivering tumor hypoxic radiosensitizing
reagents. Hypoxia is a major contributor to radio-resistance.
Thus, tumor re-oxygenation strategies, including the use of
oxygen-saturated nanomaterials (perfluorocarbon),115 oxygen-
generators (MnO2),116 NO-releasing prodrugs,117 HIF-1a
inhibitor-containing carriers,118 catalase, catalase-like metals
or H2O2,119 have been employed to address tumor hypoxia-
induced radioresistance. iii. Carrying inhibitors for DNA repair
and radioresistance signaling. Inhibitors for vital proteins
(mTOR) and signaling pathways (hedgehog signaling
or CD73/adenosine) have been incorporated into nanomedi-
cines to indirectly increase ROS deposition and augment the
microenvironmental stress.120,121 Inhibitors for DNA repair
(olaparib),122 enhancers for RT-induced apoptosis
(perifosine),123 and disrupters for the cell cycle (proflavine
hemisulfate, gemcitabine, and pentoxifylline) and the NAD+
metabolism are the family members of radiosensitizers,124,125
as they directly or indirectly improve the therapeutic
outcome of RT.
Nanomedicine-contributed assistance in radio-immuno-
therapy. Nanomedicines aid in improving the synergistic inter-
action of radiotherapy and immunotherapy. Two distinctive
approaches have been explored: one is to interfere with their
synergistic or shared signaling pathways, and the other is to
address radioresistance or immunotherapy resistance.
In the first approach, the STING pathway is one of the most
studied pathways. Generally, nanomedicines can be used to
increase RT-induced ruptured micronuclei with cytosolic DNA,
as well as deliver exogenous STING agonists, which augment
the STING activation for a robust antitumor immune response.
For instance, cGAMP/MOL, comprising a STING agonist cGAMP
and an Hf12-Ir metal organic layer, elicited robust STING
activation with low-dose radiation. Significant response from
interferon regulatory factors and excretion of STING-IFN axis-
related inflammatory cytokines (IFN-b and IL-6) were observed
after treatment with the nano-radiosensitizer compared to the
one with cGAMP alone.126 In another study, an exogenous
STING agonist, c-di-AMP, was integrated into a Mn2+ chelated
tannic acid-based nanoplatform to treat large tumors. The level
of the second messenger of STING, cGAMP, was significantly
increased by 2-fold in the 4T1 tumor tissue in this nano-
combinational treatment group in comparison with that in
the RT-treated one on day 12 post-treatment.127
Strategies for overcoming physiological barriers during
nano-medicinal delivery and addressing hypoxia, a main
factor conducive to the resistance to radio-immunotherapy,
have been employed to improve the therapeutic efficacy of
radio-immunotherapy. Briefly, modification with active target-
ing moieties, vascular normalization, and ECM normalization
are three common nanomedicine-assisted TME-modulating
methods. Tumor re-oxygenation to address hypoxia is
achieved via exogenous delivery of oxygen-generating
agents or endogenous generation promoted by delivered
reagents.
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Nanomedicine-assisted imaging. Nanomedicine-assisted
bioimaging could play a critical role in cancer radio-
immunotherapy. Its real-time in situ visual observations could
help in formulating or adjusting treatment plans, longitudin-
ally monitoring tumor progression, and acting as a predictor to
assess therapeutic response or a participator in multiple
imaging-guided precision radiation platforms.128
In contrast to current clinical routine imaging modalities,
nanomedicine-assisted imaging is devoted to improving the
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sensitivity and specificity of imaging signal of tumors under-
going radio-immunotherapy. Internal/external radiation expo-
sure may alter the immune phenotype of tumors and specific
biomarkers on the cell surface (such as PD-1, PD-L1, and
CTLA-4) or the related cells (cancer-associated fibroblast and
tumor-associated macrophages) may have thereafter been
changed.129,130 This dynamic process can be monitored with
the help of engineered site-specific probes, which consist of
corresponding targeting moieties and imaging moieties. Multi-
functional probes labelled with different signal sources could
be constructed thanks to advances in nanotechnology.131 They
can be designed to reach multiple targets or deliver multiple
imaging agents to obtain a comprehensive coverage of the
disease status. A dual positron emission tomography (PET)/
near-infrared fluorescent probe, which was prepared from 89Zr,
near-infrared fluorophore (CF-MPTMS)-attached silica nano-
particles with protamine on the surface and a heparin coating
layer, was used to in vitro label CAR T cells and in vivo track
these cells in mice models bearing ovarian peritoneal
carcinomatosis.132 Many ex vivo cell labelling methods, such
as radionuclide-labelling via copper-free click chemistry,133 and
superparamagnetic iron oxide labelling,134 have been estab-
lished to visualize immune effector T or NK cells during the
treatment process.135
Unfortunately, there is no well-defined, accurate biomarker
yet for cancer radio-immunotherapy. A few critical indicators,
such as CD8,136 granzyme B,137 and lymphocyte activation
gene-3,138 show positive correlation between their expression
and the therapeutic outcome. Additionally, the use of imaging
probes for multiple biomarkers could be a promising solution
for combination therapy. Challenges remain for interpretation
of these images and correlation of these imaging signals with
the exact therapeutic response to this combination treatment.
Support of evidence-based medicines and the use of artificial
intelligence in medical imaging analysis could help in addres-
sing these challenges.139
3.2 Design strategies of nanomedicines for radio-
immunotherapy
Elegant and rational design of nanomedicines is a critical step
for their application in radio-immunotherapy. Clinical require-
ments, preparation, and delivery routes for these nanomedi-
cines should be considered.
3.2.1 Nanoformulations for the combined therapy of RT
and immunotherapy. Many factors play a role in the application
of nanomedicines in this combined therapy, including para-
meters associated with RT (duration, dose, fraction, radiation
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type, and irradiated filed), immunotherapy (interval before or
after RT, type of administration, and immuno-oncology drugs),
and nanomedicines (functional role, formulation type, admin-
istration route, and delivery sequence). To achieve optimal
nanomedicine-assisted radio-immunotherapies, we will pre-
sent the current landscape and discuss up-to-date nanoformu-
lations and concepts in this emerging field.
Current landscape. Formulations of nanomedicines and their
potential role in the current practice of this combined therapy
are selected and shown in Table 2. The roles of these nanome-
dicines are very different depending on their formulations and
indications. They can be a nanocarrier for an exogenous anti-
gen (OVA) or a radiosensitizer to improve radiosensitivity and
overcome radiotherapy resistance, a scaffold for immunomo-
dulator drugs, or a container for in situ generated neoantigens.
As shown in Table 2, these nanomedicines not only offer
therapeutic benefits, but also act as an adjuvant medium to
enhance radio-immunotherapy.
Advances in nanoformulations for nanomedicines. A library of
cancer nanomedicines for immunotherapy or radiotherapy has
been extensively summarized elsewhere.147,148 This review con-
centrates on advances in nanoformulations for nanomedicines
that promote radio-immunotherapy.
The incorporation of a multi-functional nanocarrier into the
nanomedicine for cancer radio-immunotherapy has led to the
maximum therapeutic effect with reduced toxicity to a large
extent. Four major types of nanocarriers have been explored for
these nanoformulations: organic, inorganic, organic–inorganic
hybrid, and biomimetic nanocarriers (Fig. 4). The classification
is established on the basis of the body structure of the nano-
formulation. To note, biomimetic nanoformulations refer to
those biological products originating from mammalian cells or
bacteria, while natural or synthetic proteins are considered as
organic nanoformulations.
Liposomes, polymers, and albumin are the most widely used
organic nanocarriers in clinical drug delivery practice due to
their non-immunogenic or low-immunogenic properties
and great biocompatibility.149 In the preclinical studies, den-
drimers and natural polysaccharides have recently gained
popularity compared to other polymers. Specifically, multiva-
lent binding properties of dendrimers can be harnessed to
increase the binding kinetics of ICIs to their corresponding cell
surface receptors.150 In a recent study, hyperbranched G7
poly(amidoamide) dendrimers were conjugated with aPD-L1,
with an estimate of 3.7  0.5 antibodies per one dendrimer
and a one-order-of-magnitude increase in the binding kinetics
with PD-L1 in comparison with free aPD-L1.101 Natural poly-
saccharides, particularly hyaluronic acid, stand out for
their immunomodulatory effects.97,98 Notably, several hydro-
phobic immunological agents or radiosensitizers, such as cyclic
dinucleotides and 2-(2-nitroimidazol-1-yl) acetic acid, can act as
the hydrophobic domain in self-assembled polymeric
conjugates.151,152
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Table 2 Selected nanomedicines for combinational radio-immunotherapy

Ref. Nanoformulation RT IT Comments

Preclinical studies
Organic
Zhang et al.140 Smac-TLR7/8 peptide g-ray EBRT TLR7/8 agonist This peptide self-assembled into a nanofibrous and porous
hydrogel, overcoming the radioresistant TME and repolariz-
ing TAMs
Li et al.141 AmpFY9 peptide g-ray EBRT IDO-1 inhibitor This pH-responsive transformable peptide aided in reversing
immunosuppression via the GSH-responsive release of
NLG919
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Inorganic
Wang et al.95 4PI-Zn@CaCO3 X-ray EBRT IDO-1 inhibitor Neutralizing tumor acidity via biocompatible biomineral
CaCO3 and depleting Kyn via 4PI potentiated RT against CT26
and 4T1 tumors by inducing potent antitumor immune
response
Dong et al.142 WO2.9-WSe2-PEG NPs X-ray EBRT aPD-L1 Semiconductor-based nanoscale radiosensitizers combined
with aPD-L1 in a triple-therapy manner to treat local and
distal tumors
Organic–inorganic hybrid
Pei et al.143 177
Lu-APPs-PEG RIT RT-induced The radioactive nano-oxygen generator relieved tumor
immune hypoxia, promoted CTL infiltration, and inhibited tumor cells
response and Tregs
Sang et al.144 AHSC nanoparticles X-ray EBRT aCTLA-4; aCTLA- NP-reinforced RT and aCTLA-4 increased PD-L1 expression,
4 + aPD-L1 promoting anti-PD-L1 therapy
Biomimetic
Tian et al.145 PD-L1 siRNA loaded RGD- X-ray EBRT PD-L1 siRNA An in situ EV-mediated ICI therapy was applied to glio-
EV blastoma with short-burst radiation
Qin et al.146 Au@MC38 X-ray EBRT aPD-1 Live MC38 cell-derived biogenetic AuNPs were formed; these
Au@MC38 NPs displayed homologous targeting of tumor
cells, thus enhancing RT and immune response
Clinical trials
Liposome
NCT04580771 Liposomal HPV-16 E6/E7 EBRT Vaccine This phase II trial aimed to improve the therapeutic response
Multipeptide Vaccine against HPV-infected cervical tumors by using a liposomal
vaccine (six HPV-16 peptide-containing lipid R-DOTAP)
NCT00828009 BLP25 liposome vaccine EBRT Vaccine This phase II trial aimed to treat lung cancer with a liposomal
vaccine (lyophilization of BLP25 lipopeptide, monopho-
sphoryl lipid A, and three lipids: cholesterol, DMPG, and
DPPC) and bevacizumab after EBRT
PEG
NCT04936841 NKTR-214 (PEGylated IL-2) EBRT Immuno- This phase II trial aimed to deliver PEGylated IL-2 and aPD-1
cytokine and in combination with RT to treat head and neck cancer
aPD-1
Protein
NCT04756505 Bintrafusp Alfa EBRT Fused protein A fused protein composed of aPD-L1 and TGF-beta, an
and NHS-IL12 immunocytokine, and the protein was combined with RT to
treat breast cancer in the phase I trial
Inorganic nanoparticles
NCT05039632 Hafnium oxide-containing EBRT aCTLA-4/aPD-1 This phase I/II trial investigated the adverse effects and
nanoparticles (NBTXR3) therapeutic benefits of a combined therapy, consisting of
NBTXR3-augmented RT, aCTLA-4, and aPD-1 for metastatic
solid tumors
Abbreviations: IT, immunotherapy; IDO-1, indoleamine 2,3-dioxygenase-1; APPs, Au-Pt@PCN-224; RIT, internal radioisotope therapy; CTLs,
cytotoxic T lymphocytes; AHSC, atovaquone, hafnium, sabutoclax, and chlorin Ce6-containing metal-phenolic networks; RGD-EV, cyclic RGDyK
peptide-modified extracellular vesicles; HPV, human papillomavirus; R-DOTAP, R-enantiomer of 1,2-dioleoyl-3-trimethylammonium-propane
chloride; DMPG, dimyristoyl phosphatidylglycerol; DPPC, dipalmitoyl phosphatidylcholine.

Protein-derivatives are another essential source of organic
nanomedicines,153 which can be divided into protein-based
nanocarriers, protein-based therapeutics (e.g., antibody or anti-
genic peptide), TME-modulating enzymes, and multifunctional
hybrid proteins.154 For protein-based nanocarriers, mussel
adhesive proteins have recently emerged as an efficient nano-
carrier for localized stable retention of anti-PD-L1 because
of their substantial tissue-adhesion properties.155 Besides,
their size plays a critical role when they are delivered in a
systemic manner. In contrast to dimeric-nanobodies (anti-
HER2 2Rb17c-2Rb17c, control R3B23-R3B23, and dimeric
monovalent 2Rb17c-R3B23) and mAb (trastuzumab), mono-
meric nanobodies (2Rb17c) turned out to be the most effective
one in homogenous intratumoral distribution and rapid renal
clearance.156 In the regime of protein-based therapeutics, frag-
ments or entire antibodies/antigens can be engineered with
nanomedicines. For example, tumor antigens and Fc fragments
were fused to the C-terminal of the protein nanocarrier to form
a cancer nanovaccine, enabling DC activation and tumor-
specific targeting.157 In addition, bispecific T-cell engagers
(BiTEs) were nano-engineered with two single-chain variable
fragments (scFvs) that targeted T cells and tumor cells,

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Fig. 4 Representation of four major types of nanoformulations (organic, inorganic, organic–inorganic hybrid, biomimetic nanoformulations) that are
employed in radio-immunotherapy. (a) Organic nanoformulations. (i) Dendrimers aid in carrying immune checkpoint inhibitors or tumor antigens
released from RT-treated tumor tissues; (ii) protein-derivatives, ranging from ICIs, targeting antibodies, albumin, cytokines to adhesive proteins, are
modified with radionuclides or immunomodulatory agents via a cleavable linker to simultaneously improve the therapeutic efficacy and address their
toxicity issues; (iii) liposomes act as a conventional tool to deliver various immune-stimulation agents; (iv) polymeric nanoparticles carrying small-
molecule radiosensitizers are surface modified with ligands or therapeutic proteins via a DNA scaffold and other linkers. (b) Inorganic nanoformulations.
(i) Two representative radiosensitizers in clinical trials: hafnium oxide NPs and gadolinium-chelated polysiloxane-based NPs, (ii) various inorganic
nanoagents acting as immuno-adjuvants or carriers. (c) Organic–inorganic hybrid nanoformulations. Nanoscale coordination polymers or metal–organic
frameworks are representative structures. In these nanoformulations, metal ions can amplify local radiation and transfer energy to organic ligands upon
radiation, exacerbating ROS production. Meanwhile, immunomodulatory agents can bind to these formulations via noncovalent encapsulation or
covalent binding. (d) Biomimetic nanoformulations. Membrane-vesicles extracted from various mammalian cells or bacteria, exosomes, and fused
membranes take advantage of the unique properties of these individual cells (e.g., stealth, tumor-homing, or immune-stimulation) to realize desired
tumor control in the context of radio-immunotherapy.

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respectively.158,159 Similarly, synthetic nanoparticle antibodies
were prepared from a Janus nanoplatform with a cell-targeting
ligand on one ‘‘face’’ and a Fc-mimicking ligand on the
opposite ‘‘face’’.160 Both BiTEs and synthetic nanoparticle
antibodies were engineered onto the surface of the nanomedi-
cine with multivalent contact. In addition, a short-chain syn-
thetic DNA scaffold was demonstrated as a versatile tool to
optimize the surface of an organic nanocarrier or a cell to
strengthen the effect of their immunomodulation on immune
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cells.161 In a previous study, via complementary DNA reaction,
different therapeutic protein molecules (anti-CD3 and anti-
CD28, IL-2, or synthetic priming antigens) were ratiometrically
loaded onto the surface of poly(lactic-co-glycolic acid) (PLGA)
polymer–DNA nanoparticles. Encouragingly, this biotechnology
realized intact bioactivity of protein molecules, in vivo CAR T
activation and tumor clearance via an ‘‘AND’’ logic-gate, and
ex vivo T cell activation and expansion.162
Inorganic nanoformulations have been widely used in clin-
ical practice or trials, including aluminum salt (aluminum
hydroxide and aluminum phosphate), graphene or silica. They
act as cancer vaccine adjuvants for antigen reservoir and DC
maturation,163 as well as radiosensitizers. NBTXR3 (phase III,
status: recruiting) and AGuIX (phase II, status: recruiting) are
two examples of inorganic nano-radiosensitizers.39 In preclini-
cal studies, a great sum of inorganic nanomedicines, such as
aluminum NPs, CaCO3 NPs, metal oxide NPs (e.g., MnO2), and
mesoporous silica NPs, emerge as potent radiosensitizers,
immuno-adjuvants or carriers. These inorganic nanomedicines
exhibit high Z metal- or hypoxia relief-mediated radiation
sensitization, display inherent or acquired immunomodulatory
effects, and possess a high drug-loading capacity.164,165 In the
term of radiation sensitization, several high-Z element-based
nanomedicines with efficient nano-catalytic properties, such as
hafnium oxide, gadolinium, gold, bismuth, platinum, and
titanium oxide, have been reported to augment radiation
deposition and ROS generation.108–110,166 Besides, these inor-
ganic nanomedicines can be doped or labelled with radio-
nuclides or self-assembled from radionuclides themselves
(such as b-particle emitter 198Au) as an internal radioisotope
therapeutic agent.167 Several radiolabeling methods have there-
after been prompted. A recent study proposed a universal
chelator-free radiolabeling method, i.e., the use of a SnCl2/
HCl solution and Tween 80 for labelling therapeutic 188Re with
both inorganic (SiO2, Au, and Fe3O4) and organic (PLA) NPs
with a high labelling efficiency up to 98% and an in vitro
radiochemical stability of 95%.168 Their adjuvant roles in
immunotherapy are generally divided into two types. One is
adsorption or delivery of antigenic peptides or mRNA for a
sustained effect.169 The other one is to realize immune-
stimulation by their biological active structures. For instance,
PEGylated mesoporous silica nanoparticles with a tunable pore
diameter and a large internal surface have been previously
reported to trigger the TLR4/NF-kB pathway in macrophages
and recruit T cells to inflame cold tumors.170,171 b-alanine-
modified Gd@C82 was also demonstrated to reprogram TAMs
to the tumor-killing M1 type.172 Notably, upon external or
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internal stimulation, metal oxide-based nanoparticles can neu-
tralize tumor acidity or catalytically decompose over-expressing
H2O2 to relieve the immunosuppression in the TME (e.g.,
CaCO3 or MnO2) for enhancing the RT efficacy,95,173,174 or
generating adequate ROS to induce in situ vaccination (e.g.,
HfO2).175 More importantly, with the rapid progress of biode-
gradable strategies in designing inorganic nanomedicines,
their toxicity issues related to long-term retention and tough
clearance can be elegantly addressed.176
Metal–organic frameworks (MOFs), consisting of high Z
metal ions/clusters and coordinated organic molecules, are a
typical organic–inorganic hybrid nanocarrier used in radio-
immunotherapy. They have enjoyed a blooming growth in this
field due to their homogeneous porous structure, the radio-
sensitization effect, and their therapeutic enhancements in
vaccination and ICI treatment.177,178 For example, cationic
nMOFs were applied to deliver anionic CpGs via electrostatic
interactions to perform X-ray-activated vaccination.179 A wide
range of metal ions/clusters and coordinated organic ligands in
preparing MOFs endow this hybrid nanocarrier with a diversity
of functions. For instance, the high-Z element Hf or Bi has the
radiation amplified effect, metals (Mn, Fe) are able to act as an
imaging and immune- or redox-modulating agent, and organic
ligands such as Ir(DBB)[dF(CF3)ppy]2+, Ir(bpy)[dF(CF3)ppy]2+,
DBA, and DBP (corresponding chemical nomenclature: DBB,
4,4 0 -di(4-benzoato)-2,2 0 -bipyridine; dF(CF3)ppy, 2-(2,4-difluo-
rophenyl)-5-(trifluoromethyl)pyridine; bpy, 2,2 0 -bipyridine;
DBA, 2,5-di(p-benzoato)aniline; DBP, 5,15-di(p-benzoato)-
porphyrin) are photosensitizing.180–182 A study has witnessed
more than 99% of tumor regression in a MC38 mice model
treated with Hf-based nMOFs at a low radiation dosage of
0.5 Gy  5 fractions. Mechanistically, the secondary building
units (SBUs) of electron-dense Hf12 and Hf6 absorbed X-rays to
produce hydroxyl radicals. The generated energy was trans-
ferred to the photosensitizing ligand Ir(DBB)[dF(CF3)ppy]2+ to
produce 1O2 and O2.183 Monte Carlo simulation results
revealed that the radiosensitization effect of lattices in the
MOF exceeded solid NPs due to enhanced scattering of photons
and electrons within the lattices regardless of the radiation
source and particle size. Thus, tuning the lattice parameters,
such as the SBU size and/or the inter-SBU distance could
contribute to an optimal radiation dose.184 Meanwhile, other
inorganic–organic hybrid nanocarriers, such as organic
ligands, polymers or biomacromolecule-modified inorganic
nanoformulations could be potential candidates of radio-
immunotherapy.
Biomimetic nanocarriers have the reputation for their bio-
compatibility, the intrinsic tumor-homing effect, and inherent
immunogenic properties.185–187 A myriad of engineered biomi-
metic membrane-based vesicles (single membrane-based vesi-
cles, fused cell membrane-based vesicles, and exosomes),
originating from blood cells, platelets, tumor cells, immune
cells, and bacteria, have been utilized to deliver antigenic
agents or other therapeutic agents to elicit an immune
response in the practice of cancer vaccination or radio-
immunotherapy.188–192 These biomimetic nanocarriers provide
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a strong shelter to prevent premature leakage and enzymatic
lysis of cargos such as nucleic acids or proteins. Among single
membrane-based vesicles, one typical and prevalent applica-
tion is to use tumor cell membranes or bacteria-derived outer
membrane vesicles (OMVs) as a biomimetic coating layer to
realize targeted delivery of ICIs or radiosensitizers, as well as
immune-activation.193,194 Fused cell membrane-based vesicles
integrate characteristic biochemical receptors and surface func-
tional groups of each individual cells, and thereafter can act as
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a potent nanocarrier to achieve multiple functions in radio-
immunotherapy. For example, fusion of the cytomembranes of
mature DCs and tumor cells achieved co-expression of tumor
antigens and immunological costimulatory molecules.195 Other
hybrid vesicles have also been widely explored, including fusion
of membranes from erythrocytes and tumor cells,196 hybridiza-
tion of the membranes of macrophages and cancer cells,197 or
blending of autologous tumor cell membranes and OMVs.198
And recently, liposomes/lipid reagents or polymeric nanostruc-
tures have been introduced to cell membrane-based vesicles to
improve their stability and address their issues, such as size- or
shape-controllability and reproducibility.199,200 Lipid-bilayer
extracellular vesicles are also employed to enhance cell–cell
communication, strengthen their interaction with non-cellular
TME constituents, and deliver bioactive cargos.201,202 HER2+
extracellular vesicles from BT-474 cells were successfully
attached to the surface of MDA-MB-231 cells from triple-
negative breast cancer tissues. This tissue has no therapeutic
receptors, and the introduction of extracellular vesicles into
these cells helped in achieving targeted therapy of HER2
positive cancer.203 Immunomodulatory drugs including BDC-
1001 (TLR7/8 agonists) and pembrolizumab (PD-1 antibody),
as well as HER2-targeting radionuclide drugs (e.g., 131I-GMIB-
Anti-HER2-VHH1, 177Lu-DOTA-ADAPT6-ABD035), have been
employed in this case.204–207
Overall, the above four major types of nanocarriers, particu-
larly liposomes, protein-derivatives, inorganic radiosensitizers,
and biomimetic vesicles, have great potential in clinical trans-
lation in consideration of their drug-loading capacity, biologi-
cal safety, encouraging preliminary clinical trial results, and
acceptance by patients and doctors. Meanwhile, the interaction
between nanocarriers and biological cells, immunotoxicity, and
immunogenicity remain to be understood.208 Thus, intensive
studies on these aspects of nanocarriers should be investigated.
For instance, graphdiyne oxide as a nanocarrier helped polariz-
ing M2 macrophages to pro-inflammatory ones.209,210
3.2.2 Optimization of nanomedicine-assisted radio-immu-
notherapy. Achieving an effective localized drug concentration
in tumors and reducing non-specific distribution outside the
tumors could be hindered by several obstacles: the blood–brain
barrier, the blood-tumor barrier, a dense extracellular
tumor matrix, a high interstitial fluid pressure, non-specific
adhesion, and uptake by the liver reticuloendothelial
system.211,212 Nanomedicines can be thereafter optimized with
a few engineering strategies to overcome these above obstacles
to enhance their therapeutic efficacy in radio-immunotherapy
(Fig. 5).
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Optimization of nanomedicines. Optimization of nanomedi-
cines can be obtained by modulating their size, shape, elasti-
city, composition, surface charge, and surface chemistry.213,214
In cancer radio-immunotherapy, size-changeability and shape-
deformability were found to play an important role in deliver-
ing antitumor vaccines to lymph nodes or immunoregulatory
agents to tumors.215 It was reported that a rod-like shape of
mesoporous silica nanoparticles outperformed in targeting
tumor cells, including MCF7 cells and pancreas cancer cells
(PANC-1 cells), rather than healthy cells (MCF10A and CAFs) in
comparison with the spherical one.216 For tuning the surface
charge, a charge-reversal modification strategy by harnessing a
tumoral acidity-responsive bond that links a positively-charged
inner ligand and a neutral or negative anti-fouling outer ligand
(e.g., zwitterion polymer or PEG) has been applied to construct
a nanomedicine with negligible surface protein adsorption and
high tumor cellular uptake.217 In the case of lymphatic trans-
port, a negatively-charged nanocarrier was found to be superior
to the positively-charged one.218 Moreover, active surface mod-
ifications with sufficiently accessible ligands enhance selective
targetability of nanomedicines towards tumor cells or tumor-
associated macrophages.219,220 In one study, surface modifica-
tion of glucose moieties in generation 4 hydroxyl PAMAM
dendrimers endowed them with the targetability towards TAMs
via interaction between glucose and glucose transporters.
Meanwhile, replacement of glucose with galactose facilitated
targeting galactins on the surface of glioblastoma cells.221 In
addition, layer-by-layer (LDL) surface modification is an emer-
ging method to simultaneously allow specific targeting and
toxicity mitigation of high-dose immunocytokine therapy.
Single-chain interleukin-12 was coated onto a liposome, and
the prepared product was wrapped with a second layer of poly-L-
arginine and a third layer of poly-L-glutamic acid or hyaluronic
acid. Even at an increasing dose, a significant toxicity reduction
and an enhanced therapeutic efficiency were observed in the
treatment of this LDL-modified nanoparticle toward murine
colorectal and ovarian tumors.222
To conclude, the optimization of size, shape, structure,
surface charge or surface chemistry of nanomedicines can
endow them with the ability of loading onco-immunological
agents (tumor antigens, STING agonists, or ICD inducers) and
radio-enhancers to tumors or lymph nodes in a more safe and
effective manner.223–225
Additionally, nanomedicines can be optimized according to
their systemic or local administration routes. A high level of
drug accumulation in lesions, stability during blood circula-
tion, and a low level of distribution in normal tissues are
essential for nanomedicines in a systemic administration man-
ner. Thus, nanomedicines are often tuned or modified to have a
high drug loading, specific tumor-targetability, and resistance
to protein corona formulation. Meanwhile, for local adminis-
tration of nanomedicines via intratumoral injection, transder-
mal administration, transarterial embolization, or portal vein
embolization, they should have a prolonged residence time
with controlled release of antitumor drugs including immu-
notherapeutic agents or radiosensitizers in the region of
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interest.226 Strategies including size-tunability for local reten-
tion and chemical conjugation for prolonged retention are
preferable in the design of these nanomedicines. For instance,
in a recent study, thermal-responsive phase transition of
elastin-like polypeptides and electrostatic interaction between
their oligolysine tail and CpG were utilized to promote the
formation of a local complexation depot, achieving long-term
local retention of GpG for more than 3 weeks and therapeutic
131
I for 2 weeks.227
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immunotherapeutic agents or radiosensitizers at the target
tumor site and reducing their toxicity to normal tissues.228–232
External therapeutic radiation can be an excellent external
stimulus for controlled release of tumor antigens and immu-
notherapeutic agents in radio-immunotherapy.50 For instance,
PhotoCORM MnBr(CO)5, a photo-sensitive moiety to release CO
in a lanthanide scintillator NP (ScNPs:NaLuF4:Gd,Tb@NaLuF4),
was indirectly activated by external X-rays to subsequently
realize the release of the CO gas in a deep-tissue (about 5 cm)

and simultaneously achieve CO-mediated ROS generation and

Optimization of stimuli-responsive drug-release from nanome-
dicines. Stimuli-responsive drug release from nanomedicines
triggered by external stimuli (ultrasound, magnetic, light, or
X-ray radiation) or internal stimuli (low pH, high ROS, and
over-expressed proteases in the TME) can help in releasing
ICD.233 The common radiation-responsive chemical bonds or
structures are summarized in Fig. 5b. The underlying working
principle of radiation-responsive drug release is not well under-
stood and different mechanisms have been proposed, for
example, radiation triggered photolytic degradation of a PLA

Fig. 5 Illustration of nanomedicine optimizations based on administration routes and reported radiation-responsive bonds or structures in RT-based
combined therapies. (a) Optimization of nanomedicines via their administration routes comprise two major steps: the first step is to meet basic
requirements of nanoformulations for systemic routes or local routes; the second one is to optimize the structure and surface chemistry of
nanomedicines to realize protein resistance, size/shape/charge transformation, active targeting, and controlled release. (b) Optimization of radiation-
responsive drug release: the mechanism scheme and a group of reported radiation-responsive bonds or structures in RT-based therapies.

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polymer.234,235 In another case, g-rays triggered the cleavage of
hydrogen bonds between the antitumor drug, pemetrexed, and
cytosine-containing diselenide in diselenide-pemetrexed
assemblies, and the released drug activated NK cells and
exerted its antitumor activity.236 ROS-sensitive bonds can also
respond to g-ray radiation since they induce ROS generation.
For example, hydrophobic poly-(propylene sulfide) was
reported to be oxidized to hydrophilic sulfoxides/sulfone in
the presence of OH that was generated upon g-ray radiation,
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and a robust release of encapsulated drugs was achieved during
the oxidation process.237
Optimization of administration routes for nanomedicines. The
administration routes of nanomedicines into the body can be
categorized into systemic delivery (intravenous or oral admin-
istration) and localized supply (intra-tumoral, intra-nodular,
transdermal, intra-peritoneal, intranasal, or intraocular admin-
istration). As reported, the ability of inducing vaccination via
intradermal/subcutaneous injection, intramuscular injection,
and i.v. injection/oral administration of nanomedicines is in
the descending order.238
The optimal administration route for a nanomedicine is
heavily dependent on its therapeutic mechanism and the
characteristics of indications.239 It is suggested that cancer
nanovaccines should reach lymphatic sites to augment the
presentation of antigens to APCs, the maturation of APCs,
and the activation of antigen-specific cytotoxicity T cells. There
are two major routes for delivery of nanomedicines into lym-
phatic sites: direct access through parenteral injection (sub-
cutaneous and intradermal), or mucosal administration
(enteral, pulmonary, and intravaginal).240 The sequence of
administration is essential to the final vaccination effect. In a
recent study, simultaneous or sequential intravenous/subcuta-
neous (IV/SC) vaccination was carried out using antigen/CpG-
loaded layered double hydroxide nanoparticles in a tumoral
murine model bearing E.G7-OVA-lymphoma or B16F10-
melanoma. The antitumor effect of IV-priming + SC-boosting
was much stronger than that of the untreated group, and more
than 75–90% of the tumor volume shrank after sequential
IV/SC vaccination. Simultaneous IV/SC injection of this cancer
nanovaccine contributed to a one-week delay of tumor progres-
sion to the end point when the tumor volume reached
1000 mm3 in both tumor models at an early-stage with an
initial volume of 50 mm3 and a late-stage with an initial volume
of 500 mm3, respectively.241
3.2.3 Determination of indications and preclinical models
for radio-immunotherapy. To date, oncology-related indica-
tions have been trialed with radio-immunotherapy and their
corresponding murine cellular lines are listed in the brackets,
including non-small cell lung cancer (LLC), melanoma (B16-
F10, Cloudman S91), prostate cancer (TRAMP-C2), colon carci-
noma (MC38 and CT26), liver cancer (rabbit VX2, H22, and
Hepa 1–6), triple-negative breast cancer (4T1, EMT6, and
TUBO), and bladder cancer (MB49).241,242 Very impressively, a
map of intratumoral changes at the single-cell level indicated
that triple-negative breast cancer, the most aggressive form of
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solid tumors among all breast cancers,243 has the highest
number of tumor-infiltrating lymphocytes during the anti-
PD1 treatment of 40 breast cancer patients.244 Metastatic
melanoma and lung cancer with a high mutation rate may be
a better candidate for this combined radio-immunotherapy
since it facilitates neoantigen discovery and selection.245,246
Meanwhile, glioblastoma, characterized with a low nonsynon-
ymous mutation rate and insufficient infiltration of immune
cells in tumors,247 is not sensitive to conventional RT or
immunotherapy, but it may be effectively treated with
nanomedicine-mediated radio-immunotherapy.
Intensive studies have been devoted to establishing and
selecting in vitro/in vivo models for evaluating the therapeutic
potency of nanomedicines for radio-immunotherapy. Ideal
models should be able to map the actual tumor microenviron-
ment in the human body, including the immune system.
Discoveries from these models could accelerate clinical transla-
tion. While, in reality, a cancer tissue consisting of tumor cells
and at least one immune cell population from a systemic-
stimulated mouse model (genetically-engineered or therapy-
induced) are often selected to determine the therapeutic effi-
cacies of radio-immunotherapy.
Generally, animal tumor models consist of subcutaneous- or
orthotopic-grafted cancer, metastasis-induced cancer (intrave-
nous or intracardiac engraftment), and artificially induced
spontaneous cancer.248 The orthotopic animal model offers a
biomimicking tumor microenvironment similar to that of the
original cancer development. A transgene-driven model may
provide a great insight on early oncogenesis and tumor
mutation-induced neoantigens, while a carcinogen-driven
model can display constitutional heterogeneity in tumor
tissues.249 Notably, the selection of the mouse species is a
crucial parameter in evaluating the effectiveness of cancer
radio-immunotherapy. It has been found that C57BL/6 mice
prefer to developing Th1 immune response, which is vital to
CD8+ T cell-participated antitumor immune response.250
Hence, C57BL/6 mice species is widely used for evaluating the
efficacy of radiotherapy and immunotherapy. The ratio of M1/
M2 phenotype of TAMs varies among mice models and it is
higher in the model bearing 4T1 murine breast cancer than the
model with CT26 tumors.118 In addition, these cancer models
should be reproducible and practical to be built. Tracking of
the cell lineage could be essential to realize reproducibility.251
In the preclinical trial of treating cancer with radio-
immunotherapy, bilateral tumor models and re-challenged
tumor models are the most frequently used. To develop a re-
challenged model for a prophylactic nanovaccine against can-
cer or pre-immunization, the nanovaccine or an immune-
stimulation agent is primarily injected into the left and right
footpads of mice models. After seven-day immunization, cancer
cells are subsequently injected.252 It has been reported that the
efficacy of the vaccine depends on the survival rate of the
injected cancer cells. Additionally, thanks to rapid progress of
microfluidic chips, in vitro silico-based models, such as patient-
specific glioblastoma models, have been established as a robust
predictive tool for radio-immunotherapy.253
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However, there are very few reliable, reproducible and
cheap models covering metastasis, cancer prevention, tumor
dormancy or quiescence, and immune- or radiation-resistance.
More importantly, due to inherent limitations, the animal
models used in most pre-clinical studies on radio-
immunotherapy are murine cell line-derived models, not
human tumor-originated ones. Three emerging humanized
murine models for immune-oncology-based therapy, including
the Hu-PBL model, Hu-CD34 model, and BLT model, have been
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potency and biosafety of nanomedicine-assisted caner radio-
immunotherapy can be properly and widely assessed.
4. State-of-the-art nanomedicine-
assisted cancer radio-immunotherapy
Nanomedicines have assisted in cancer radio-immunotherapy
in two major aspects. One is that nanomedicines have aided in

built on immunodeficient mice via injection of human periph-
eral blood mononuclear cells (PBMCs), human CD34+ hemato-
poietic stem cells, and human fetal liver and thymus along with
stem cells, respectively.254 However, these humanized models
suffer from a few issues: induction of a severe graft-verse-host
disease, inability to induce MHC-restricting tumor antigen-
specific immune response, and a complex modeling
process.255 Efforts should be devoted to building models to
capture accurate and dynamic biological information of human
cancer tissues while maintaining accessibility so that the
in vitro diagnosis, in vivo pre-selection, real-time monitoring,
and evaluation of the therapeutic response of cancer patients.
They have also contributed to increasing the therapeutic effi-
cacy and reducing toxicity. Their state-of-the-art advances are
summarized in Table 3.
4.1 Nanomedicine-assisted imaging for radio-
immunotherapy
Imaging cancer tissues is an integral part of cancer treatment and
it has been realized through a wide range of nanomedicines. For

Table 3 Representative examples of nanomedicine-assisted radio-immunotherapy

Main function Interventions Remarks Ref.

Pre-stratification and
response assessment
Nanovaccine and in situ
cancer vaccination
Prompting ICD
Overcoming therapy
resistance
Reducing therapy-induced
toxicity
Abbreviations: IO, iron oxide; aiMRI, activatable inflammation magnetic resonance imaging; OVA, ovalbumin; SPG, Shirasu porous glass;
RP@RMs, irradiated cancer cell membrane coated on R837-loaded PLGA; Phy@PLGdH, physcion@layered gadolinium hydroxide; GDYO,
graphdiyne oxide; NIA, 2-(2-nitroimidazol-1-yl) acetic acid; AuDAP, dual-functional Au nanoparticle; CLIO, cross-linked dextran iron oxide.
64
Cu-labeled polyglucose NPs Tumor associated macrophage imaging; 256
Monitoring TAM response to adjuvant therapy;
Correlating imaging intensity with TAM densities.
68
Ga-NOTA-Nb109 Nonblocking imaging of PD-L1. 257
ROS-responsive IO-Gd Early stratification of RT response;
nanovesicle aiMRI approach is developed;
Acute oxidative stress bridge antitumor immunity. 258
Bi2O3@OVA@DC + RT OVA as a synthesis template for Bi2O3 NPs; 259
Improved efficiency compared with OVA@DC;
Augmenting the STING signaling by Bi2O3 NPs.
PLGA/CpG@PDA-Au + RT Rapid SPG membrane emulsification; 89
Radio-sensitization;
In situ capture of RT-induced antigens.
RP@RMs Irradiated tumor cell membranes as a vaccine; stronger 54
immunogenicity of RMs.
Phy@PLGdH nanosheets + RT + Shape affecting radiation deposition; 260
aPD-L1 Nanosheets outperforming spherical one;
Inhibiting the pentose phosphate pathway.
H@Gd-NCPs + RT + aPD-L1/ Radiation deposition & GSH depletion; 261
aCTLA-4 Decomposition of H2O2 by Hemin;
Sensitized RT potentiating ICI therapy.
Hf-CpG MXF + RT CpG as DNA components of MXF; 262
Maintaining long-term immune-memory.
GDYO nanosheets Inherent immunomodulatory properties; 210
Polarizing M2- to M1-type TAMs;
Stimulating NF-kB & MAPK pathways.
NIA-D1@R848 + RT NIA reducing radioresistance of hypoxia cells;
D
PPA-1 relieving suppression of T cells. 263
AuDAP + RT Dual targeting with AS1411 aptamer & M2pep;
Repolarizing M2 to M1 via NF-kB signaling axis. 264
Masked IL-12 Protein domain as a mask agent; 96
Tumor protease-cleavable linker;
Encouraging efficacy without systemic irAEs.
Three click-antidote: Ab-antidotes derived from NPs; 265
phospholipid-PEG micelles, BSA, Short-circulating CLIO NPs perform better than other two
CLIO NPs + click-antibody clicked NPs and CLIO nanoworms.
Polydopamine NPs Oral administration; 266
Scavenging ROS and suppressing inflammation; curing RT-
induced intestinal injury.

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cancer radio-immunotherapy, nanomedicines have effectively
helped pre-selecting patients for this treatment, assessing ther-
apeutic response of patients during the treatment, and identifying
immune-related adverse events (irAEs). Furthermore, in vivo ima-
ging biomarkers of cancer tissues or tumor-infiltrating immune
cells could provide guidelines for preparing nano-formulations to
achieve effective radio-immunotherapy in pre-selected patients.
4.1.1 Pre-stratification of patients for radio-immu-
notherapy. Pre-stratification of patients can help in avoiding
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ineffective treatment, preventing delays in therapeutic inter-
ventions, and reducing undesirable adverse effects.267 In this
context, imaging helps semi-quantitative analysis of character-
istic components in the TME, such as tumor-associated macro-
phages and tumor-infiltrating lymphocytes.268 Imaging also
reveals tumor kinetics/dynamics for evaluating the extracellular
matrix (ECM) density and the enhanced permeability and
retention (EPR) effect. The vasculature density can be observed
by serial imaging, and these EPR-indicated radiographical
features are crucial for patient stratifications in nanomedicine-
assisted treatment.
Nanomedicine-assisted imaging strategies for pre-
stratification of patients include: (a) imaging the expression
of biomarkers that are associated with positive therapeutic
outcomes, (b) monitoring dynamic changes in biomarkers
upon therapeutic interventions at a stimulating dose for rapid
pre-evaluation of a treatment plan, and (c) assessing the
accumulation level of therapeutic agents in the tumor
tissue.269 These obtained images can help in initially discrimi-
nating responders from non-responders towards radio-
immunotherapy. Among all imaging modalities, nuclear med-
ical imaging techniques, such as PET and single photon emis-
sion computed tomography (SPECT), have ultra-high imaging
sensitivity and are a preferred choice for imaging in radio-
immunotherapy.270 In detail, radionuclides emit b+ or g rays for
PET or SPECT imaging signal, respectively, as well as b or a
rays for radiation therapy. These radionuclides can be chelated
to a nanomedicine to diagnose and pre-stratify cancer patients
simultaneously.271 For instance, PET imaging of intercellular
adhesion molecule-1, an up-regulated inducible glycoprotein in
non-irradiated tumors in mice receiving RT, can be a valuable
tool to pre-select patients with the ‘‘abscopal effect’’ at an early
stage.272
A sum of factors, such as a high tumor mutational burden, T
cell-inflamed gene expression, PD-1/PD-L1 expression, muta-
tions in the repair or correction pathways for DNA damage or
mismatch, and microsatellite instability, have been taken into
consideration as reliable clinical biomarkers, as well as inde-
pendent indicators to jointly stratify human cancer to some
extent.273–275 In a recent report, an anti-hPD-L1 heavy chain-
only antibody, Nb6, was labelled with a PET signal-emitting
radionuclide, 124I, to select positive-responsive responders in
an osteosarcoma OS-732 tumor for the following anti-PD-L1-
based immunotherapy. This Nb6 antibody with a high affinity
for hPD-L1 was first selected from 95 monoclones with the help
of phage display technology. 124I-anti-hPD-L1 displayed a high
binding affinity value (2.19 nM) towards OS-732 cells in vitro
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and an accumulation amount of 4.43  0.33% ID g1 in the OS-
732 tumor tissue at 24 h post-injection in vivo, confirming its
biological effect on its application in bioimaging.276 In another
study, 64Cu-labelled polyglucose nanoparticles, termed as
Macrin, were constructed for quantitative analysis of TAMs
via imaging; this probe with a size of B20 nm exhibited a high
selectivity (490%) towards macrophages. Since the amount of
a radionuclide-labelled model drug accumulated in TAM-rich
tumors was more than 7-fold that of TAM-deficient tumors, this
TAM-monitoring approach showed a potent ability of pre-
selecting patients (Fig. 6a).256 In whole, imaging PD-L1 expres-
sion on tumor cell and the infiltration density of TAMs is
currently the most feasible pre-stratification strategy for
immuno-based therapy.
Tumor biomarkers in different cancer types, such as tissue
factors and L1-cell adhesion molecules, have also been explored
as promising pre-selection targets in assessing the accumulation
level of nanomedicines at the tumor sites. The tissue factor (TF)
was chosen as a potential target for anaplastic thyroid cancer.
ALT-836 as a TF-specific mAb was thereafter developed. According
to quantitative flow cytometry analysis, ALT-836 displayed a much
higher level of cellular uptake in TF-abundant THJ-16T cells than
TF-deficient TPC-1 cells. Its radionuclide-labelled derivative, 64Cu-
NOTA-ALT-836, was reported to achieve high accumulation in
subcutaneous and orthotopic ATCs; the peak of tumor uptake
reached 19.93  2.17% and 37.20  1.71% ID g1 in subcuta-
neous and orthotopic models, respectively (Fig. 6b).277 The L1-cell
adhesion molecule (L1CAM) in cholangiocarcinoma was investi-
gated in another study. A diagnostic radioisotope, 64Cu, was
conjugated to NH2-terminated chimeric anti-L1CAM (cA10-A3)
through a bifunctional chelator, 2-S-(4-isothiocyanatoenzyl)-1,4,7-
triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA). In vivo
biodistribution of 64Cu-NOTA-cA10-A3 (37 MBq/100 mg) peaked
with 18.9  2.6% ID g1 at 48 h post-injection at the SCK-L1
tumor site, while its tumor accumulation was much lower in other
mice tumor models (Choi-CK, SCK, and JCRB1033). The in vivo
imaging result was in line with the in vitro cell-bound assay and
the L1CAM expression level in these cell lines, which was con-
firmed from western blotting and flow cytometry analysis, indicat-
ing the feasibility of using this 64Cu-NOTA-cA10-A3 probe for
detecting L1CAM-positive patients.278
In summary, nanomedicine-assisted imaging strategies
broaden the way to pre-select patients for nanomedicine-
based radio-immunotherapy. Moreover, classification methods
to distinguish tumor immune states have emerged, such as
transcriptomic-based analytical platforms for TME subtypes
and tumor immunity in the microenvironment.279,280 These
methods may dramatically accelerate the discovery of specific
and sensitive biomarkers for pre-stratification of cancer
patients and facilitate the development of their corresponding
nanomedicine-assisted imaging probes.
4.1.2 Response assessment. Decision on the continuation,
suspension, or modification of radio-immunotherapy depends
on patients’ response, including biomarker levels from multi-
ple sources (blood, lymphatic system, and tumor tissues),
specific radiographic manifestations, and clinical symptoms.
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Fig. 6 Pre-stratification of murine tumor models through nanomedicine-enabled PET imaging of tumor-associated biomarkers. (a) 64Cu-labelled
polyglucose nanoparticles were constructed for quantitative analysis of tumor-associated macrophages: (i) the chemical structure of this probe and its
working principle; (ii) PET/CT imaging of KP lung adenocarcinoma-bearing C57BL/6 mice at 24 h post-injection of this probe. Reproduced with
permission. Ref. 256 Copyright 2018, American Chemical Society. (b) A 64Cu-labelled tissue factor-specific mAb was developed to image tissue factors:
(i) flow cytometry confirmed a high level of the tissue factor in THJ-16 anaplastic thyroid cancer (ATC) cells; (ii) representative maximum intensity
projection (MIP) images of orthotopic ATC murine models using 64Cu-NOTA-ALT-836. Reproduced with permission. Ref. 277 Copyright 2020 the
Authors, Published by Wiley-VCH.

In general, the response patterns to cancer radio-
immunotherapy can be defined as follows: hyperprogression,
pseudoprogression, stable disease, partial response, and com-
plete response.281
A clear, early understanding of tumor response to therapies
in holistic cancer treatment is essential to improve clinical
outcomes. The nanomedicine-assisted in vitro diagnosis
approach and in vivo functional imaging emerge as powerful
and timely tools for evaluating and predicting body response to
radio-immunotherapy. Because of a relatively slow therapeutic
response towards radiotherapy and immunotherapy due to
changes in tumor size, invasion, and metastasis, this
nanomedicine-mediated approach can unveil timely, accurate
and specific information about tumor tissues after RT treat-
ment, such as dynamic changes in immune cell infiltration and
early indicators (e.g., elevated ROS or caspase-3).258,282
Circulating tumor DNA (ctDNA) acts an early evaluation
indicator for in vitro diagnosis and provides valuable prognostic
information about patients treated with antitumor immu-
notherapy and/or radiotherapy.283,284 A feasible approach for
the in vitro detection of ctDNA could be the use of
nanomedicine-aided detection probes, such as gold nano-
particles and DNA nanomedicines.285 However, the prognostic
value from in vitro detection is restricted due to a lack of unified
criteria for sampling time, sampling location, multi-biopsy, and
tumor heterogeneity,286 while in vivo nanomedicine-mediated
imaging is free from these limitations. It can provide accurate
immune profiles of patients and its non-invasive imaging
features cause less harm to the body.
PD-L1 (B33 kDa) is recognized as a well-known biomarker
for radio-immunotherapy. After RT intervention, it is highly
expressed in tumor cells and antigen-presenting cells to realize
immune escape, which may facilitate aPD-L1 therapy.20,287 A
diagnostic radionuclide 89Zr-conjugated anti-PD-L1 (atezolizu-
mab), was utilized in a recent clinical study to image 22
patients. Each patient had one unique tumor and there were
three different tumor types among 22 patients including meta-
static bladder cancer, non-small cell lung cancer, and triple-
negative breast cancer. Compared to immunohistochemistry
(IHC)- or RNA-Seq-based in vitro predictive biomarkers, the
generated PET signal from this 89Zr-labelled mAb was better
correlated with the therapeutic responses.288 In a previous pre-
clinical study, 89Zr-desferrioxamine(Df)-atezolizumab was
employed for non-invasive quantitation of PD-L1 expression
after RT treatment. Two lung cancer cell lines, PD-L1+ H460
cells and PD-L1 A549 cells, were selected in this study. After

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delivering external RT (5 fractions of 2 Gy) to tumor sites, tumor
uptake of 89Zr-Df-atezolizumab in PD-L1+ H460 bearing mice
was significantly increased, while its uptake was slightly
improved in mice models with PD-L1 A549 cells. Of note, this
RT treatment significantly improved the PD-L1/b-actin ratio by
nearly six fold in H460 cells. These results suggested that the
PD-L1 expression was upregulated after RT, and this 89Zr-
labelled antibody could be used to monitor the change in PD-L1
expression.289 Moreover, some engineering strategies haven
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domain antibody with a different binding epitope from that
of anti-PD-L1 and a chelated PET tracer (68Ga-NOTA), was
applied to quantitatively assess PD-L1 expression in tumors.
Successfully, this probe had a relatively high equilibrium dis-
sociation constant of 2.9  109 M and a maximum uptake
ratio of 5.0  0.35% ID g1 could be achieved in A375-hPD-L1
tumors at 1 h post-injection (Fig. 7a).257 Therefore, PD-L1
peptide antagonists that do not affect the binding of PD-L1
antibodies could be explored to modify imaging probe-labeled

been developed for PD-L1 targeting. In one report, a
radionuclide-labelled lipid-PD-L1 aptamer was applied for the
immunoimaging of PD-L1. A 99mTc-labelled and PD-L1
aptamer-modified C18 chain (C18-apPDL1) was constructed
and exhibited two-fold tumoral accumulation at 24 h post-
injection (about 0.88% ID g1) compared to the PD-L1 aptamer
and a random sequence-modified C18.290 Notably, nonblocking
imaging of PD-L1 on tumor cells, a novel and advanced imaging
method, emerges and allows real-time monitoring of PD-L1
expression without interfering with the PD-L1 blockade-based
therapy. 68Ga-NOTA-Nb109, composed of a specific single-
or non-labeled immunomodulatory nanomedicines after RT
treatment.
Other emerging technologies, including multiple
biomarker-targeting multimodal probes and radiomic analysis,
allow biomarker-driven predictions of tumor response to radio-
immunotherapy. A dual PET/SERS imaging nanoprobe was
used to simultaneously detect PD-L1+ tumor cells and CD8+ T
cells (Fig. 7b). A Raman reporter, 5,5-dithiobis(2-nitrobenzoic
acid) with a peak wavenumber at 1325 cm1 or para-
mercaptobenzoic acid with a feature peak at 1580 cm1, was
incorporated on the surface of gold nanostars through a thiol–

Fig. 7 PET imaging via nano-probes aids in accurate and specific monitoring of therapeutic responses towards immune-related therapies. (a)
Nonblocking PET imaging of PD-L1 using 68Ga-NOTA-NB109: (i) illustration of the nano-probe and its working principle; (ii) dynamic PET imaging of
three murine tumor models using this nano-probe. Reproduced with permission. Ref. 257 Copyright 2020, Society of Nuclear Medicine and Molecular
Imaging. (b) Dual-model surface-enhanced Raman spectroscopy (SERS)/PET imaging of PD-L1 and CD8+ in immuno-oncology-treated YUMM2.1
tumors via an engineered immunoactive probe prepared from gold nanostars: (i) scheme of the preparation process of this nano-probe; (ii) SERS spectra
of murine tumor models receiving anti-CD137 + anti-PD-L1 treatment and an IgG control, as well as their corresponding SERS quantification; (iii) PET-CT
imaging of the treated groups at 24 h post-injection of this nano-probe and their corresponding PET quantification. Reproduced with permission. Ref.
291 Copyright 2019, American Chemical Society.

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Au reaction. Correspondingly, PEGylated anti-CD8 or anti-PD-
L1 was then conjugated to gold nanostars, followed by DOTA
chelator conjugation and 64Cu chelation. After seven days from
the initial treatment of both PD-L1 and CD137 agonists, two
immunoreactive gold nanostars (IGNs) were injected to moni-
tor the response towards immunotherapy. This treatment was
repeated three times and the administration of IgG was set as a
control. PET/CT imaging revealed a relatively high level of
tumor accumulation of IGNs in the combinational treatment
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group (0.58% ID g1) compared to that in the IgG-treated
control group (0.31% ID g1). Furthermore, the averaged SERS
spectral intensity in the treated and control groups supported
that much more CD8+ T cells were seen in the treatment group,
which was consistent with the immunohistochemistry staining
result via 3,3 0 diaminobenzidine, an agent for CD8+ T cell-
specific immunostaining. In all, this imaging platform provides
a versatile scaffold for multiple biomarker-specific imaging.291
In another study, novel radiomic analysis based on quantitative
imaging after incorporation of iodixanol-encapsulated lipo-
somes was employed to assess myeloid-derived suppressor cell
(MDSC)-directed immunotherapy. A prolonged blood circula-
tion time and a high level of nanoparticle accumulation
in perivascular regions facilitated spatiotemporal visualiza-
tion of MDSC-influenced vascular structures. Furthermore,
nanoparticle-mediated CT images were extracted for radiomic
analysis, and the results indicated that the texture-based fea-
ture was helpful in differentiating treatment groups.292
Inspried by these findings, it could be inferred that dual
targeting of MDSCs or M2-like TAMs could be valuable to
determine the therapeutic resistance at the tumor site. Dual
targeting strategies to inhibit these cells have been demon-
strated to improve the antitumor therapeutic efficay,293,294 and
depletion of both of them was reported to poteniate the ICI
therapy,295 indicating the benefit of imaging both MDSCs
and TAMs.
Pseudoprogression and hyperprogression are two typical
outcomes in radio-immunotherapy, which are multiple factor-
driven and not fully understood yet. It is reported that the
overall incident rate of pseudoprogression is less than 10% in
cancer patients receiving ICIs, for instance, 6.4% in patients
with melanoma, 5% in patients with NSCLC, and 7% in
patients with genitourinary cancer.296 Five major hypotheses
are proposed for pseudoprogression, including (a) Treg expan-
sion; (b) T-cell exhaustion; (c) modulation of pro-tumorigenic
immune subsets; (d) oncogenic-pathway activation; and (e)
aberrant inflammation.297 Meanwhile, hyperprogression refers
to two distinct pathophysiologic phenomena: (1) rapid tumor
progression may not be correlated with immune checkpoint
inhibition; and (2) accelerated tumor growth may be induced by
ICI-related premature death (e.g., apoptosis).298 With regard
to its multiplex imaging and specific-targeting properties,
nanoprobes may be an effective strategy to aid in the non-
invasive discrimination until more relevant biomarkers have
been found.
Overall, these advanced technologies, including in vitro
diagnosis of circulating biomarkers or in vivo non-invasive
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advanced imaging tools, can provide a precise and clear land-
scape of tumor response to radio-immunotherapy. Neverthe-
less, one should note that not all these indices have clinical
significance and some of them can only be applied to disease-
specific evaluation. Meanwhile, a few principal endpoints such as
overall survival, progression-free survival, and time to form new
metastases may be overestimated for radio-immunotherapy, and
other endpoints for radio-immunotherapy should be explored for
better evaluation of the therapeutic outcome.
4.2 Cancer nanovaccine-participated radio-immunotherapy
Cancer nanovaccine-mediated vaccination, including exogen-
ous vaccination, in situ cancer vaccination (ISV), or both, has
emerged as a hot topic in cancer research to eradicate residual
cancer tissues after surgical treatment, induce tumor regres-
sion and durable antitumor immune response, and prevent
tumor progression.299,300 Currently, three major categories of
clinically-available personalized cancer vaccines are whole cell
lysates of DCs, synthetic long peptides, and mRNA.301 So far,
there are two clinically-approved therapeutic cancer vaccines:
Bacillus Calmette-Guerin (BCG) for early-stage bladder cancer
and Sipuleucel-T (Provenge) for prostate cancer, and a few
preventive cancer vaccines against HPV-induced cancer (Cer-
varix, Gardasil, and Gardasil-g) or hepatitis B virus-induced
cancer (HEPLISAV-B).302 The nanomedicine-based biological
negative or biological active vaccination adjuvants, which are
beyond conventionally-used liposomes or lipidoid nano-
particles, along with RT, a potent inducer of ISV,303 have been
demonstrated to boost innate or adaptive antitumor immune
response and increase the therapeutic efficacy by improving
antigenicity and adjuvanticity.304–307 Their working principle is
concisely demonstrated in Fig. 8.
Exogenous cancer vaccination is realized by cancer nano-
vaccines that carry model antigens or identified antigens. These
nanovaccines carrying identified antigens are ready for large-
scale production and clinical translation since these biological
active agents are well understood. In contrast, individualized
in situ vaccination relies mainly on the antigens from immuno-
genic dying tumor cells induced by radiation therapy or other
therapies.308 Treatments, such as radiotherapy, Bacillus
Calmette-Guerin, TLR agonists, oncolytic viruses, immune
cytokines, and Doxil, can elicit in situ cancer vaccination.309
Compared with exogenous cancer nanovaccines, this in situ
vaccination approach can avoid a complex preparation proce-
dure, possible contaminations, and immune tolerance induced
by the use of universal tumor-associated model antigens.
Notably, antigen-capturing nanoparticles, such as maleimide-
modified dendrimers or bacteria outer membrane vesicles and
dopamine-coated PLGA polymeric nanoparticles, aid in form-
ing in situ cancer vaccination by capturing antigens released
from the above therapy-treated tumors.89,90
Several typical nanomedicines derived from polymers,
MOFs, tumor-derived membrane-based vesicles or exosomes,
or radionuclide-labelled ones are presented below and their
potent vaccination effects are discussed.
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Fig. 8 Scheme for underlying mechanisms of exogenous and in situ cancer vaccination induced by RT-aided cancer nanovaccines. (a) Engineered
nanomedicines are i.v. or i.t. administrated to the body for capturing and presenting RT-induced released tumor antigens. (b) Tumor membrane vesicles
isolated and extruded from RT-treated in vitro tumor cells or in vivo tumor tissues are utilized as personalized cancer nanovaccines. (c) RT primes the
tumor microenvironment, contributing to a preferable condition for exogenous cancer nanovaccine-initiated immune response.

Polymers, including micelles, polymer–epitope conjugates,
and lipid–polymer hybrids, are the leading nanocarriers for
cancer vaccination apart from liposomes. A pH-responsive
PC7A nanovaccine, consisting of E7 or OVA antigenic peptide-
loaded polyethylene glycol-b-poly(2-hexamethyleneimino ethyl
methacrylate), was developed by Gao et al. for treating a size-
able solid tumor by incorporating local RT (20 Gy). In the tumor
mice model of TC-1 (murine lung cancer) and B16-OVA (murine
melanoma cancer), this combined treatment exhibited a sig-
nificant volume reduction in both primary and distal tumors
via systemic and local STING-activation mechanisms.310 Their
following study on a library of melanoma antigens (Trp1,
Tnpo3, Obsl1, Pbk, and Gp100) revealed that phase transition
of these antigen structures from random coils to a-helix con-
tributed to efficient antigenic peptide loading in PC7A micelles,
which may provide a new means of selecting peptide antigens
for nanovaccines.311 In another study, this PC7A polymer was
applied to combine with CpG, while maleimide-decorated
bacterial membrane was coated on them to form an in situ
vaccine. This antigen-capturing nanoparticle aided in absorb-
ing released neoantigens from tumor tissues after RT interven-
tion and then cross-presenting to lymph nodes for subsequent
DC maturation and CTL infiltration.312 In summary, the tun-
able physiochemical properties of polymer-based nanovaccines
allow improving antigen transportation to immune follicles or
tumors and protecting antigens from pre-degradation or rapid
clearance.
A high-Z element-containing MOF is a potent nanostructure
candidate for boosting exogenous and in situ cancer
vaccination, which is primarily attributed to its porous and
hollow structure for holding antigens or immune-stimulating
agents, as well as its radio-sensitization effect to aid in RT-
induced in situ vaccination.313 Two nanoscale MOFs, DBP-Hf
and DBA-Hf, were prepared from an Hf cluster and a porphyrin-
based photosensitizer ligand, 5,15-di(p-benzoato)porphyrin
(DBP) and 5,10,15,20-tetra(p-benzoato)porphyrin (DBA), respec-
tively. These prepared MOFs were applied to deliver an
INCB024360 analogue, an IDO inhibitor, to realize synergistic
radio-immunotherapy via an in situ vaccination approach. Both
nanomedicines, IDOi@nMOF, exhibited distinctive radiation
enhancement factors: 2.13–3.36 for DBP-Hf and 1.47–1.66 for
DBA-Hf, in comparison with 1.00–1.22 for HfO2 at the same Hf
concentration. Intratumoral injection of the IDOi-loaded DBP-
Hf MOF in combination with low-dose X-rays (0.5 Gy  6
fractions) to treat bilateral murine breast cancer (TUBO) and
colorectal cancer (CT26) demonstrated a superior antitumor
effect.177 In a similar study, anionic CpG was loaded on the
surface of a cationic nMOF with a photosensitizing ligand via
electrostatic interaction to obtain Hf-DBBF-Ir@CpG. Intratu-
moral injection of this nanomedicine and local X-ray irradia-
tion were applied to a primary tumor during the treatment
process. In situ vaccination was initiated by CpG incorporated
in Hf-DBBF-Ir@CpG as a pathogen-associated molecular pat-
tern agent and released agents (DAMPs and tumor neoanti-
gens) from tumor cells induced by this treatment.
Consequently, this approach efficiently activated antigen-
presenting cells and facilitated the infiltration of cytotoxic T
cells in tumor regions in immunosuppressive murine colorectal

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MC38 and pancreatic Panc02 models. When this treatment was
combined with aPD-L1, the cure rate reached 83.3% in a T cell-
absent MC38 model.179 One major advantage of MOFs is easy
and broad modulation of their compositions (metal ions,
organic ligands, and loaded agents) to realize different pur-
poses. In a recent study, MRI-visible Mn2+ was chosen as
metal ions, meso-2,6-diaminopimelic acid (DAP), a nucleotide
oligomerization binding domain 1 agonist, was selected as
organic ligands, and ovalbumin (OVA) acted as a model anti-
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gen. The combination of these compositions achieved an
imaging-guided nanovaccine delivery to B16-OVA melanoma
tumors.314
Tumor cell membranes or tumor-derived exosomes isolated
from X-ray irradiated tumor cells could be employed as perso-
nalized nanovaccines due to their upregulated expression of
MHC-I, IFN-g, and tumor neoantigens.54,315 For instance, sub-
cutaneous injection of microvesicles at an average size of
339.9  139.0 nm produced from irradiated C6 glioma cells
at a single dose of 50 Gy led to 450% tumoral volume
reduction in a subcutaneous glioma C6-bearing rat model
compared to the group treated with microvesicles at a size of
395.0  202.6 nm from cells without irradiation. Apoptotic tumor
cells in the irradiated microvesicle-treated group were three times
higher than in the control group, thus the predominant antitumor
mechanism of this irradiated microvesicle-based vaccine was
attributed to apoptosis of tumor cells.316
In addition to the above external radiation-participated
vaccination methods, injection of therapeutic radioisotope-
incorporated nanomedicines is another practical and feasible
approach to induce in situ vaccination. Clinically available 131I
was selected as an internal radiation source, and alginate
(ALG), a natural polysaccharide as an endogenous Ca2+-
responsive gelation and fixed agent, was chosen to locally hold
131
I-labelled catalase (CAT) and an immune-adjuvant CpG
oligonucleotide at the tumor site. This ‘‘vaccine-alike’’ 131I-
CAT/CpG/ALG displayed excellent immune memory pro-
tection with no apparent secondary tumor growth. No animal
death was observed until the end observation time point
at day 90. The percentage of effector memory T cells
(CD3+CD8+CD62LCD44+ T cells) in the spleen and the level
of cytokines (TNF-a and TNF-g) in the serum were significantly
higher in CT26 tumor models treated with 131I-CAT/CpG/ALG
than those treated with surgery and 131I-CAT/ALG.317 In another
study, 131I-MnO2-BSA was systemically administered to CT26
murine colorectal tumor models. Compared with other thera-
pies (control, MnO2-BSA, and free 131I), this radionuclide-based
nanoformulation contributed to a 1–3-fold increase in matured
DCs and a 1–2-fold increase in CD3+CD8+ cytotoxic T cells at the
tumor sites.318
Overall, there remain a few challenges in this vaccination-
mediated treatment. There may be a potential risk for in situ
vaccination: burst release of tumor-associated antigens that are
also expressed in non-tumoral tissues may result in nonspecific
enhanced immune response to healthy tissues. Exogenous
nanovaccination involves multiple procedures including load-
ing tumor neoantigens, transporting to lymph nodes, maturing
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DC, and activating cytotoxic T lymphocytes. It is challenging
for an exogeneous nanovaccine to be effective in these multiple
procedures. Thus, cancer nanovaccines usually have insuffi-
cient vaccine potency for tumor eradication, and they are
often accompanied by other therapies, including ICIs or
chemotherapeutic drugs.
4.3 Prompting immunogenic cell death (ICD)
ICD is referred to cell death that elicits an immune response by
recruiting and activating DCs to antigens released from dead or
dying tumor cells.319,320 ICD is often induced after physical/
chemical stresses on the endoplasmic reticulum and it is
featured with a high production level of ROS and an apoptotic
cell morphology that maintains membrane integrity.321,322 ICD
inducers either prompt tumor cell death or induce the release
of DAMPs. They are normally divided into two main types: type
I acts as an ROS generator; and type II exerts escalated collateral
stresses on the endoplasmic reticulum.323 Besides, the hall-
marks of ICD are exposure of calreticulin (CRT) and heat shock
proteins on the cell surface, active release of high mobility
group protein B1 (HMGB1) and ATP, and late-stage presenta-
tion of uric acid.324,325 ATP provides a ‘‘find me’’ signal to
recruit DCs. The DC phagocytoses the generated ERp57/CRT
complexes to offer an ‘‘eat me’’ signal through their interaction
with CD91, a DC receptor, and the NF-kB pathway to produce
IL-6 and TNF-a. Notably, ICD is also strongly correlated with
cancer vaccination.326,327
Among ICD inducers from a physical energy source, such as
a magnetic field,328 ultrasound,329 and near-infrared light,330
RT is the most accessible, acceptable, and well-studied ther-
apeutic modality in clinics. When immunotherapy is intro-
duced simultaneously, RT outperforms other inducers.
Specifically, RT holds the following advantages: (a) deep tumor
penetration; (b) high power energy;331 (c) localized therapeutic
radioisotopes for internal radioisotope therapy that can mimic
an irradiation field to reduce damage to normal tissues;332 (d)
imaging-guided precise therapy via one integral instrument
(IGRT or MR-Linac);333,334 (f) tunable biological effects induced
at different doses;21,22 and (g) routine use without sensitizers.
In the context of radio-immunotherapy, RT induces upregu-
lated expression of tumor antigens and inducible or constitu-
tive DAMPs,335 but it generates too weak an effect to elicit
sufficient ICD due to several endogenous resistance mechan-
isms and poor radiation absorption in some of tumor tissues
(e.g., sarcoma).336 Insufficient ICD or low immunogenicity is
also often seen in conventional ICI-based immunotherapy.337
The use of nanomedicines can boost the effect of ICD in radio-
immunotherapy by either delivering adequate immune adju-
vants to elicit strong immune response or escalating the anti-
tumor effect of radiation, thus enhancing the therapeutic
efficacies of immunotherapy. Cisplatin-loaded poly(L-glutamic
acid)-graft-methoxy poly(ethylene glycol) complex nanoparticles
(CDDP-NPs) were reported to significantly enhance RT-induced
ICD. The percentage of CRT-positive Lewis lung cancer cells
increased from 16.47% by treatment with RT to 27.03% after
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treatment with RT + CDDP-NPs, in comparison with 20.53% in
the group treated with RT + cisplatin.338
A few nanosized ICD inducers, including nanoscale coordi-
nation polymers, high Z radiosensitizers, and natural polysac-
charides, have been developed in combination with strategies
of amplifying oxidative stress to induce a boosted ICD effect.
Nanoscale coordination polymers (NCPs) in which ROS-
generating metal ions (e.g., Hf, Gd, Cu, or Bi) are incorporated
into functional ligands or biomacromolecules (CpG oligodeoxy-
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nucleotides) have been reported to induce potent ICD via an
elevated ER stress.262,339 For instance, in a recent study, gado-
linium and zoledronic acid self-assembled to form a nanorod-
like NCP, ZGd-NRs, with a long and short diameter of 200 and
20 nm, respectively. Evaluation of intracellular ROS and g-H2Aw
in CT26 cells indicated that ZGd-NRs could efficiently amplify
ROS generation and enhance X-ray deposition. The incorpo-
rated Gd3+ ions accounted for most of the radio-sensitization
effect. The CT26 cells treated with ZGd-NRs and RT displayed a
1–4-fold increase in the ICD induction indicators including the
level of CRT, HMGB1, and ATP in comparison with other three
groups treated with saline, ZGd-NRs, and saline + RT. When the
treatment with ZGd-NRs and RT was combined with aPD-L1,
the infiltrated CD4+ and CD8+ T cells in both primary and
distant tumors were nearly doubled. Furthermore, the func-
tional ligand, zoledronic acid, helped in depleting TAMs to
reprogram an immunosuppressive TME by causing apoptosis
of macrophages (Fig. 9a).340 Another strategy to boost potent
ICD was recently proposed. Mixed-valence copper (Cu+/Cu2+)
was chosen as a metal ion candidate. 5 0 -Guanosine monopho-
sphate (5 0 -GMP), widely presented in the body, acted as a
coordination ligand for this Cu-NCP. Amplified oxidase stress
was attributed to a synergistic effect via Cu+-mediated ROS
generation and Cu2+-triggered GSH elimination. This nanome-
dicine in combination with RT increased CD8+ cell infiltration
and IFN-g expression in a 4T1 murine breast model. Further-
more, in a 4T1 primary and metastatic tumor model, the
addition of aPD-L1 showed a better antitumor effect and a
greater level of biosafety than other control groups, as evi-
denced by the primary tumor volume, the mice body weight,
counts of lung metastatic sites, and the survival percentage
(Fig. 9b).341 Similarly, gadolinium, 5 0 -GMP, and hemin (a
peroxidase mimic), self-assembled to form H@Gd-NCPs.
Hemin has a similar function to Cu2+, utilizing overproduced
H2O2 to deplete GSH via peroxidase-mimic catalytic activity.261
To conclude, NCPs offer a versatile scaffold or model carrier for
a vast library of ICD-inducing ligands, metal ions and immune-
activation agents.
High-Z element radiosensitizers contribute to an enhanced
performance of RT-induced ICD. They generate ROS in an
intracellular oxygen-independent manner, contributing to the
amplification of the endoplasmic reticulum stress, a crucial
inducer for ICD.342 A snowflake-like Au nanocarrier with RT-
responsive degradability, S-AuNC, was constructed to load anti-
PD-L1. Under X-ray irradiation, the high-Z gold-based nanos-
tructure produced a high ROS level, which irreversibly disin-
tegrated the structure to release the loaded anti-PD-L1. Among
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all the treatment groups on murine Tramp C1 prostate cancer
cells, RT plus S-AuNC induced sufficient ICD with a
HMGB1+CRT+ cell population of 51.4%, in comparison with
37.4% in the group treated with RT. Additionally, the PD-L1
expression in the RT + S-AuNC-treated group was significantly
increased by nearly 4 fold compared to that in the RT group,
facilitating the following therapy with released anti-PD-L1
from the nanomedicine.343 Similarly, a heterojunction
WO2.9–WSe2–PEG nanostructure (WSP NP) with high photo-
catalytic activity was developed to boost the intracellular ROS
level, which could induce ICD. It was noticed that the high
photocatalytic properties of this heterojunction structure
were ascribed to the inherent properties of the high-Z ele-
ment and the heterojunction structure because this structure
was able to prevent the recombination of electrons and holes.
The fluorescence intensity of ROS generated in the group
treated with WSP NPs and X-rays was strengthened by 1.5
times compared to that in the X-ray-treated group. Confocal
imaging and flow cytometry also confirmed sufficient induc-
tion of an ICD biomarker, CRT, in 4T1 cells treated with WSP
NPs and X-rays.142 To conclude, high-Z nano-radiosensitizers
can be used to prepare potent nanoformulations for promot-
ing induction of ICD through increasing the ROS-mediated
endoplasmic reticulum stress under low-dose external irra-
diation. Moreover, these nano-radiosensitizers in combi-
nation with ICIs could significantly improve antitumor
immune response.
Natural polysaccharides including chitosan, hyaluronic
acid, dextran, alginate, and Ganoderma lucidum polysaccharides
have been reported to be immunoactive and promote DC
maturation, a critical immunogenic indicator of ICD.98,344 For
example, sulfhydryl-modified Ganoderma lucidum polysacchar-
ides (GLP) were covalently conjugated to bismuth sulfide
nanoparticles (BiNPs) to prepare GLP-BiNPs. BiNPs were
synthesized via a BSA-mediated template approach. DC matura-
tion was then investigated in the spleen/tumor of 4T1 breast
tumor-bearing mice treated with a negative control, BiNP, and
GLP-BiNP. In contrast to groups treated with BiNP and the
control, the percentages of mature DCs in the tumor/spleen at a
post-injection time point of 24 h or 72 h were higher in the mice
group receiving GLP-BiNP. In the group treated with 4 Gy X-ray
radiation at 4 h after intravenous injection of GLP-BiNP, the
tumor volume was effectively reduced compared to other
groups treated with a negative control, GLP-BiNP, X-rays, and
BiNP + X-rays. The percentage of CD4+/CD8+ T cells in spleno-
cytes and the concentration of IFN-g and IL-4 in the group
treated with GLP-BiNP + X-rays were significantly higher than
those in other treatment groups.345 In another study, the
Astragalus membranaceus polysaccharide was reported to induce
DC activation through the TLR4 signaling pathway.195 Since the
potential bio-effect induced by these immunoactive agents is
very promising, their biological mechanism and biosafety
should be examined in great detail, such as the triggered
signaling pathways for inducing immune activation and the
intensity, durability, and universality of induced immune
activation.
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Fig. 9 Nanoscale coordination polymer-based ICD inducers for improving antitumor therapeutic outcomes. (a) Zoledronic acid–gadolinium coordina-
tion polymer nanorods (ZGd-NRs) aided in improving radio-immunotherapy: (i) scheme of the preparation procedure and TEM images of ZGd-NRs;
three typical ICD biomarkers in CT26 tumor cells, (ii) CRT, (iii) HMGB1, and (iv) ATP, upon four different treatments (saline, ZGd-NRs, saline + RT,
ZGd-NRs + RT). Reproduced with permission. Ref. 340 Copyright 2021, American Chemical Society. (b) Mixed-valence copper-based nanoscale
coordination polymers (Cu-NCPs) for augmenting radio-immunotherapy: (i) preparation process and TEM images of Cu-NCPs; (ii) synergistic
mechanism of Cu-NCPs with RT to promote ICD; (iii) growth curves of distant tumors and (iv) counts of lung metastases sites in tumor-bearing murine
models after various treatments including saline, Cu-NCPs + RT + aCD8a, aPD-L1 + RT, Cu-NCPs + RT, and Cu-NCPs + RT + aPD-L1. Reproduced with
permission. Ref. 341 Copyright 2021, Wiley-VCH.

Overall, the approaches to using NCPs, radiosensitizers,
or natural polysaccharides to escalate the tumor ROS
level and induce ICD-related immune response have been
demonstrated to be able to induce potent ICD. At present,
RT-induced ICD is vastly studied in cancer radio-
immunotherapy, while a few studies focus on the
potential role of mono-immunomodulator agents as the
ICD inducer.
4.4 Overcoming resistance to radio-immunotherapy
Biological or pathological barriers, insensitivity to radiation
therapy, and immunosuppression are three major resistances

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to cancer radio-immunotherapy. These three resistances are
tightly interwoven due to their common drivers, such as
hypoxia and myeloid-derived suppressor cells. As a result,
biological or pathological barriers are addressed to mitigate
the resistance to radio-immunotherapy in most cases, and
mitigation in the radiation resistance may be accompanied by
the effect of reversing immunosuppression, and vice versa.
4.4.1 Addressing biological or pathological barriers to
radio-immunotherapy. Before active drugs arrive at the sites
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peptide, Cys–Arg–Glu–Lys–Ala peptide, and twin arginine trans-
location peptide), small molecules (e.g., folic acid, biotin,
mannose, galactose, and sialic acid), and other active targeting
ligands (e.g., epithelial cell adhesion molecule aptamer, diben-
zocyclooctyne, and hyaluronic acid) have been used for improv-
ing accumulation and retention of nanomedicines in the region
of interest. This strategy is well summarized elsewhere.350,351
To cross the brain–blood barriers, recently, an adenosine 2A
receptor agonist has been reported to affect both F-actin and

of interest, there exist a number of different barriers along their
delivery paths. These barriers can be divided into two types:346
one is physiological barriers, such as the blood–brain barriers
in the treatment of malignant brain lesions and nonspecific
accumulation in the liver reticuloendothelial system,347,348 and
the other is disease-specific, for example, the presence of
few blood vessels in large tumor burdens, a dense, highly
desmoplastic extracellular tumoral matrix, and blood vessel
compression.349
To address the physiological barriers, active targeting moi-
eties are often incorporated or conjugated onto nanomedicines
for precision therapy (Fig. 10a). Antibodies/nanobodies (e.g.,
anti-epidermal growth factor receptor and anti-human
epidermal growth factor receptor-2), peptides (e.g., intercellular
adhesion molecule-1 peptide, arginine–glycine–aspartic acid
tight junctions of endothelial cells, and it could be a potential
immunotherapeutic candidate for active targeting of brain
malignancies.352 Similarly, an ApoE-peptide-modified polymer-
some was shown to successfully penetrate the blood–brain
barrier in a mimicking in vitro model, a bEnd.3 murine
endothelial cell monolayer. Furthermore, its immunoregulatory
cargos (granzyme B and CpG) contributed to a prolonged
survival duration in orthotopic glioma-bearing mice.353 In
addition, an in vivo click chemistry-mediated approach was
reported by harnessing the interaction between pre-azide
group-modified lymphatic endothelial cells and a dibenzo-
cyclooctyhne-functionalized cancer nanovaccine to increase
the accumulation of the nanovaccine in the lymph node.354
Furthermore, pre-occupying the sites in the liver reticuloen-
dothelial system is another approach to improving active

Fig. 10 Scheme for three major strategies of addressing barriers in nanomedicine-assisted radio-immunotherapy. (a) Active targeting of cell-based
vesicle or nanocarrier is realized by surface modification with peptides, aptamers, tumor cell membranes, click agents, antibodies, small molecules, and/
or carbohydrates. (b) Vascular normalization is achieved through nitric oxide-releasing agents, low-dose radiation, inhibition of the IGFBP7-CD93 axis or
anti-VEGF, use of folic acid (FA)-modified gold NPs, and copper depletion and aggregation. (c) ECM normalization is achieved by depleting cancer-
associated fibroblasts, inhibiting hyaluronan and collagen via various strategies. Abbreviations: ICAM-1, intercellular adhesion molecule-1; CREKA, Cys–
Arg–Glu–Lys–Ala; EPCAM, epithelial cell adhesion molecule; TCO, trans-cyclooctene; DBCO, dibenzoazacyclooctyne; VEGF, vascular endothelial
growth factor; ECM, extracellular matrix; FAP, fibroblast activation protein; PDAC, pancreatic ductal adenocarcinoma; HBO, hyperbaric oxygen.

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targeting and bioavailability of drugs.355 In summary, these
active targeting strategies, such as cancer nanovaccines
targeting lymph nodes and radiosensitizers or nano-
immunomodulators targeting the TME,356–358 could enhance
the accumulation of the nanomedicines to exert their biological
effects.
Besides RT-aided blood flow improvement, strategies of
using nanomedicines for vascular normalization and ECM
normalization are conducive to addressing the disease-specific
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barriers.359,360 Vascular normalization could be achieved by
utilizing antiangiogenic agents (e.g., anti-VEGF and nitric
oxide-based prodrugs) or other therapeutic interventions (e.g.,
low-dose radiation) to address issues originating from abnor-
mal tumor vasculature, allowing adequate perfusion of medic-
inal drugs and tumor oxygenation (Fig. 10b).361 These
therapeutic benefits are often dose- and time-dependent.362 It
was reported that blocking the insulin-like growth factor-
binding protein 7 (IGFBP7)/CD93 axis using mAbs in two mice
models, an orthotopic KPC tumor model and a B16 tumor
model, contributed to tumor vascular normalization, which in
turn sensitized tumor cells to ICI therapy.363 Besides, folic acid-
incorporated gold nanoparticles (AuNPP-FA), composed of
folate, a PEG block, a PDEAEA block with tertiary amines,
and stabilized gold nanoparticles, were applied to normalize
the tumor vascular structure through strengthening tight junc-
tions by upregulating the VE-cadherin level and increasing the
pericyte coverage. Notably, a correlation between tumor vascu-
lar normalization realized by AuNPP-FA and tumor metastasis
inhibition was established, indirectly supporting the potential
effect of vascular normalization on reducing metastasis.364 In
another report, imidazole-incorporated organosilica nanoche-
lators with a copper/phosphate responsive aggregation beha-
vior were developed to realize antiangiogenesis and vascular
obstruction after depleting Cu2+. An elevated level of Cu2+ and
phosphate in the tumor environment was significantly reduced
because the coordination interaction between imidazole or
phosphate and Cu2+ led to aggregation of these dispersed
sub-6 nm nanochelators. A significant antitumor effect was
achieved in both 4T1 breast cancer and CT26 murine colon
cancer models after treatment with nanochelators compared to
other groups treated with saline or a copper chelator TM in the
clinical trial.365
ECM normalization regulates the dense, aberrant tumor
ECM and vessel compression, enabling homogenous distribu-
tion and enhanced penetration of nanomedicines (Fig. 10c).
Abundant cancer-associated fibroblasts (CAFs), collagen I, and
hyaluronan may be the main therapeutic targets. CAF, a driver
for fibrosis generation, matrix remodeling and immune cross-
talk, may exert negative effects on radio-immunotherapy and
hence become a leading therapeutic target.366 Specific targets
and inhibitors for CAFs have been discovered. Cyclopamine, a
sonic hedgehog inhibitor, was reported to deplete stroma-
producing CAFs in a polymeric micelle nanoformulation.367
Fibroblast activation protein (FAP) that is overexpressed in
CAFs was reported to be successfully targeted by nanomedi-
cines modified with a quinoline-based FAP-inhibitor variant
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(FAPI-46).368,369 Moreover, SLC7A11, a cystine transporter in
pancreatic ductal adenocarcinoma (PDAC) tumor stroma-
derived CAF, was identified to be independently prognostic of
poor overall survival. A gene-silencing nanomedicine against
SLC7A11 was thereafter developed and proved to be able to
reduce tumor growth, CAF activation, and fibrosis in orthotopic
murine PDAC models.370 For stroma-rich collagen and hyalur-
onan, a significant decrease in ECM levels (e.g., collagen) in 4T1
metastases nodules was recently observed after the treatment of
tranilast and liposomal Doxil. Specifically, the fraction areas of
collagen I, hyaluronan, and hypoxia in this treatment group
were significantly reduced, while the density of the perfused
vessels increased in contrast to other treatment groups. As a
result, this nanomedicine-induced vessel decompression effect
resulted in an elevated antitumor effect of ICI in two
immunotherapy-insensitive metastatic breast cancer models
(4T1 and E0771).371 In addition, hyperbaric oxygen (HBO)
therapy could leverage high-pressure oxygen (2.5 atm) to over-
come stroma-rich solid tumors, including PDAC, hepatocellular
carcinoma, and triple-negative breast cancer, through depleting
main components of the extracellular matrix (collagen) via
multiple mechanisms, such as downregulating the gene of
TGF-b as well as the genes related to the CXCL12/CXCR4
signaling axis and disrupting hypoxia-mediated immunosup-
pression. Thus, this physical therapy may be a potential addition
to current nanomedicine-assisted radio-immunotherapy.372
4.4.2 Overcoming resistance to radiation therapy. Radia-
tion resistance, featured with tumor relapse, progression, or
spread after RT, remains one major obstacle in cancer radio-
immunotherapy. From a theoretical point of view, tumor
hypoxia, altered mitochondrial metabolism and energy genera-
tion, immune evasion, inflammation, and the presence of
cancer stem cells may be the major constitutional factors for
the radioresistant phenotype of tumors.373
Hypoxia is the primary factor that leads to radiotherapy
insensitivity or radiation resistance because the indirect DNA-
damaging effect of RT predominantly relies on oxygen in the
TME.374 Hence, improving tumor oxygenation or enhancing
oxygen-independent free radical generation are two promising
approaches for relieving hypoxia-induced radioresistance in the
TME. Improving tumor oxygenation can be realized by increas-
ing intratumoral blood flow, delivering or generating oxygen,
and reducing the expression of hypoxia-inducible factors (e.g.,
HIF-1a) in the TME.375 The use of a high-Z radiosensitizer for
selective RT irradiation on hypoxia tumor regions or a nano-
catalyzer (e.g., catalase and holo-lactoferrin) contributes to
oxygen-independent free radical generation.376,377
Exogenous oxygen carriers, for instance, hemoglobin (Hb)
and perfluorocarbon (PFC), as well as in situ oxygen generators,
like the combined use of H2O2 and catalase, have been
employed for tumor re-oxygenation to relieve hypoxia for
radio-immunotherapy.115 PFC@lipo, Hb@lipo, and PX-478, a
HIF-1a inhibitor, were investigated on their hypoxia relief
performance. Hb@lipo treatment was found to be the best
among these three candidates because of its more moderate
oxygen release, a higher level of tumor accumulation through
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systemic administration, and a safer profile compared to the
other two treatments.118 In another study, Hb, a high-Z radio-
sensitizer (hafnium, Hf), gallic acid, a natural metal chelator,
and catechol/Ce6-modified 8-arm PEG, self-assembled into
Hb@Hf-Ce6 nanoparticles. The fluorescence intensity of the
generated 1O2 by Hb@Hf-Ce6 nanoparticles under X-ray irra-
diation (8 Gy) was 7.29 times higher than that of free Ce6,
indicating this combined strategy achieved a synergistic ROS-
generating effect. Furthermore, treatment with Hb@Hf-Ce6 +
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RT + anti-PD-1 in a bilateral 4T1 murine breast tumor model
and its lung metastatic model exhibited remarkable control of
tumor progression and an apparent reduction in lung
metastasis.378 Moreover, a polydopamine-NP-stabilized oxygen
microcapsule was also investigated as a new oxygen carrier to
alleviate tumor hypoxia. Oxygen was sheared into microbub-
bles, and dopamine was then oxidized in an alkaline environ-
ment. Amino-rich polylysine and chitosan were used to aid in
accelerating the interfacial polymerization of dopamine nano-
particles. Finally, glutaraldehyde was used for the permanent
cross-linking of these NPs. Immunohistochemistry results
showed that the expression of HIF-1a, an indirect indicator of
the hypoxia degree, was much lower in the hep1–6 murine
tumor mice group treated with local oxygen microcapsules and
local oxygen microcapsules + RT (8 Gy  2 fractions) in
comparison with other groups, indicating that oxygen micro-
capsules could effectively relieve tumor hypoxia.379
Catalase (CAT), a nano-catalyzer and an in situ oxygen
generator, can catalytically accelerate the decomposition of
H2O2 into oxygen at the tumor site. External delivery of CAT
and H2O2 into tumors can contribute to robust tumor oxygena-
tion. For instance, CAT@liposome and H2O2@liposome were
intravenously injected into 4T1 murine breast tumor-bearing
mice in sequence at a 4 h interval. The hypoxia positive areas in
ex vivo immunofluorescence staining images of tumors after
different treatments were semi-quantitatively assessed. The
percentage of hypoxia was 61% for the group treated with
PBS and 63% for the group treated with H2O2@liposome, while
it reduced to B27% and B9% for the group treated with
CAT@liposome and CAT@liposome + subsequent H2O2@lipo-
some, respectively. As a result, the tumor oxygenation method
via CAT@liposome + subsequent H2O2@liposome significantly
improved the antitumor effect after treatment with radio-
immunotherapy (X-rays + anti-CTLA-4).380 A similar improve-
ment in tumor re-oxygenation was observed in a PLGA-
R837@CAT nanoparticle. In this nanoparticle, water-soluble
CAT was encapsulated into the core of PLGA, and a TLR-7
agonist, imiquimod (R837), was loaded onto the shell of PLGA.
Cancer radio-immunotherapy of a subcutaneous CT26 model
and an orthotopic 4T1 metastasis model via X-rays + aCTLA4
resulted in a distinctive antitumor effect after application of
PLGA-R837@CAT nanoparticles.381
Additionally, nitric oxide (NO), an exogenous regulating
agent, aids in relieving tumor hypoxia by modulating angiogen-
esis. A few NO donors, including sodium nitroprusside,383 S-
nitrosothiols,384 D-arginine,117 L-arginine,385 DETA NONOate,386
and 3-morpholinosydnonimine hydrochloride,387 have been
Chem. Soc. Rev.
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successfully used to prepare NO-generating nanomedicines to
alleviate tumor hypoxia. A NO-generating micelle was formed
via self-assembly through thin-film hydration from D-a-
Tocopheryl polyethylene glycol 1000 succinate (TPGS)-NO. Under
a high GSH tumor environment,388,389 this micelle could release
NO in a reductive-responsive manner. In vivo PET-CT imaging
with a hypoxia-specific probe (18F-MISO) confirmed that TPGS-NO
and TPGS-NO + RT could effectively reduce tumor hypoxia regions
in LLC tumor-bearing mice. Consistently, immunofluorescence
imaging and western blotting analysis demonstrated a significant
decline in HIF-1a and Glut1 expression in tumor tissues after i.v.
injection of TPGS-NO (50 mg kg1) every two days in the first week
and RT (8 Gy) on day 5. Consequently, this TPGS-NO + RT
approach contributed to a pronounced antitumor effect over other
groups treated with PBS, TPGS-NO, and RT.390 D-Arginine, another
source of NO, was loaded onto the surface of hyaluronic acid-
modified MIL-100 (Fe) to form HA@MOF/D-Arg, which was used
to improve the radiosensitivity of K7M2 murine osteosarcoma. It
was shown that by down-regulating HIF-1a expression, tumor
hypoxia was alleviated in the mice group treated with HA@MOF/D-
Arg + X-rays. More importantly, the lung metastasis sites of
osteosarcoma were found to be significantly reduced compared
to other treatment groups including PBS + X-rays, D-Arg + X-rays,
and HA@MOF + X-rays. In addition, this combined therapy
demonstrated an encouraging tumoricidal effect over other thera-
pies. The control of tumor growth was found to be in a descending
order of HA@MOF + X-rays, D-Arg + X-rays, and PBS + X-rays
(Fig. 11a).117 In another report, a 32P-labelled single-layer 2D
nanosheet, ZnNO(32P), was fabricated using Zn ions, sodium
nitroprusside (Na2Fe(CN)5NO) as a NO donor, and 32P radio-
isotopes. In their design, the therapeutic radioisotope 32P with
b-ray emission efficiently activated water to generate strong
Cerenkov luminescence (CL) and subsequently triggered NO
release. Radioisotope tracing and CL intensity monitoring in the
tumor suggested that the tumoral retention time of
intratumorally-injected ZnNO(32P) was slightly longer than that
of ZnCN(32P) but much longer than that of free 32P. Meanwhile,
this sustainable NO-releasing strategy significantly improved the
hypoxia-mediated immunosuppressive tumor environment. The
immunofluorescence images of tumor slices from different mice
groups confirmed that the tumors treated with ZnNO(32P) exhib-
ited the smallest HIF-1a and Treg positive areas and the highest
CTL positive area or the highest CTL/Treg ratio. Furthermore, the
combinational treatment with ZnNO(32P) and anti-PD-1 elicited a
potent and durable immune response. The CTL positive percen-
tages in local and distant tumors in a CT26 colon tumor model
were the highest after this combinational treatment. Meanwhile,
the concentrations of immunomodulators, including IFN-g and
TNF-a, continuously increased and they surpassed those in other
groups including PBS, anti-PD-1, and ZnNO(32P) on day 0, day 7,
and day 12 (Fig. 11b).382
Overall, nanomedicines have been developed for tackling
tumor hypoxia and other radio-resistance factors to precisely
deliver/generate oxygen, nitric oxide, HIF-1a inhibitors, radio-
sensitizers, or other similar functional agents in the tumor
hypoxia region. Besides, strategies to overcome radioresistance
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Fig. 11 NO-generating MOFs for enhancing radio-immunotherapy through sensitizing the TME. (a) D-Arginine-loaded MOFs increased the radio-
sensitivity of osteosarcoma: (i) illustration of the synthetic route for HA@MOF/D-Arg; (ii) scheme of the radio-sensitization mechanism via HA@MOF/D-
Arg; (iii) free radicals and (iv) NO gas generated from HA@MOF/D-Arg, which were measured from the intensity of their specific in vitro probes;
(v) antitumor effects of the combination therapy of HA@MOF/D-Arg with X-ray RT (indicated with arrows), PBS + X-ray, D-Arg + X-ray, and HA@MOF + X-
ray were used as controls. Reproduced with permission. Ref. 117 Copyright 2021, Elsevier. (b) 32P-Labelled ZnFe(CN)5NO nanosheets aided in improving
radioisotope-immunotherapy: (i) illustration of the lattice structure, cerenkov luminescence-induced NO release, and TME priming effect of 32P-labelled
ZnFe(CN)5NO nanosheets; (ii) immunofluorescence images of tumor slices after various treatments. Blue DAPI for cell nucleus, and green HIF-1a for
hypoxia; (iii) released NO concentrations from ZnNO(32P), ZnNO, and free 32P at different incubation time points; quantitative analysis of (iv) HIF-1a
positive area and (v) CTL/Treg ratio in tumor slices resected from murine tumor models at 12 h post-treatment with various agents, including PBS, ZnNO,
free 32P, ZnCn(32P), and ZnNO(32P). Reproduced with permission. Ref. 382 Copyright 2019, Elsevier.

of tumors have been formulated. For example, dual blockage of
RT-induced upregulated CD47 and HER2 eliminates radiore-
sistant HER2+ breast cancer.391 However, challenges remain to
be addressed, including rapid diffusion and clearance of gas
(oxygen and nitric oxide), a low amount of gas generated from
these nanomedicines, and delivery of these nanomedicines to
the tumor hypoxia regions that are often located far from blood
vessels.
4.4.3 Reversing immunosuppression. Absence of T cells or
insufficiency in T cell infiltration, recruitment and accumula-
tion of myeloid-derived suppressor cells (MDSCs), as well as the
presence of hypoxia, hypermetabolism, regulatory T cells
(Tregs) and prostaglandin E2, the loss of MHC-I molecules on
tumor cells and IFN-g sensing, and vascular occupation or
compression result in immune evasion and resistance to
immunotherapy.392–395 Moreover, tumor indications, including
glioblastoma and liver metastasis, have been frequently
described as immune resistant.396,397
Inhibiting TAMs, MDSCs, or Tregs. TAMs, MDSCs, and Tregs
are critical drivers for immunosuppression in tumors.398 TAMs
include pro-tumoral M2-like macrophages in a large population
and anti-tumoral M1-like macrophages in a minor
population.399 Depleting or reducing the recruitment of M2-
like TAMs, MDSCs, or Tregs has been demonstrated to success-
fully reverse immunosuppression.400–403
TAM-depleting bisphosphonates, a clinically-used drug,404
were reacted with calcium ions via a reverse microemulsion
method. The product was modified with PEG for labelling with
diagnostic or therapeutic radioisotopes. Cationic 99mTc4+ was

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labelled onto this nanomedicine with a radiolabelling yield of
70% by coordination between technetium and phosphonate for
single photon emission computed tomography imaging, while
32
P, in the form of anionic 32PO43 as a pharmaceutic active
ingredient, was labelled via anion exchange. This radiolabelled
CaBP(99mTc4+)-PEG nanomedicine displayed a potent tumor-
homing ability with a tumor uptake amount of 5.4% ID g1 at
24 h post-injection. The F4/80-positive area for TAMs was
significantly reduced to 0.23% after CaBP-PEG treatment in
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BP, respectively. Furthermore, the addition of therapeutic
radioisotope 32P to CaBP-PEG NPs showed an excellent syner-
gistic antitumor effect with a combination therapeutic index of
0.48. These results confirmed that CaBP-PEG NPs could effec-
tively deplete TAMs and offer a favorable tumor microenviron-
ment for the following radiotherapy (Fig. 12a).405
In an attempt to deplete MDSCs, chitosan/poly(g-glutamic
acid) nanoparticles, Ch/g-PGA NPs, were developed as a func-
tional adjuvant to RT. RT was used to reduce the primary tumor

comparison with 10.74%, 11.3%, and 3.67% in the groups
treated with PBS, CaP-PEG, and free BP, respectively. Similarly,
the TAM-stimulated EGFR-positive area shrank to 35% in the
CaBP-PEG-treated group in comparison with 67%, 64%, and
52% in the control groups treated with PBS, CaP-PEG, and free
burden, while Ch/g-PGA NPs were applied to decrease spleno-
megaly and lung metastases and relieve systemic immunosup-
pression. Consequently, the percentage of immunosuppressive
myeloid cells (CD45+CD11b+) in the spleen and the weight of
the spleen in the 4T1 tumor-bearing mice group were

Fig. 12 Nanomedicine-assisted approaches to eliminating or polarizing TAMs. (a) Chelator-free, radionuclides-labelled calcium bisphosphonate
enhanced cancer radiotherapy through depleting TAMs: (i) illustration of the preparation procedure of radio-labelled CaBP-PEG nanoparticles; (ii)
release of bisphosphonate (BP), a macrophage-depleting agent, from this NP under different pH conditions; quantitative analysis of (iii) F4/80-positive
and (iv) EGFR-positive areas in tumor slices from a murine tumor model after different treatments; (v) tumor growth curves of different treatment groups
upon administration two times indicated with arrows below the horizontal axis. Reproduced with permission. Ref. 405 Copyright 2018, American
Chemical Society. (b). Gadofullerene (GF-Ala) nanoparticles repolarized TAMs into M1-type ones: (i) scheme of the synthetic route for GF-Ala; (ii) the flow
chart of a co-culture cell system and quantitative analysis of M1 or M2 markers-associated protein expression after different incubation conditions.
Reproduced with permission. Ref. 172 Copyright 2020, American Chemical Society. (c) Triangle-shaped tellurium nanostars enabled TAM repolarization
to potentiate radio-immunotherapy: (i) illustration of the preparation procedure of GTe at different reaction durations, as well as its biological function; (ii)
the percentage of M2-type TAMs in the tumor and spleen tissue under different treatments. Reproduced with permission. Ref. 406 Copyright 2020,
Elsevier.

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reduced.407 In a murine model of GL261 glioma, the PD-L1 level
in tumor-associated myeloid cells (TAMCs), including M-
MDSCs, PMN-MDSCs, and TAMs, was found to be the highest
compared to other glioma-infiltrating immune cells (microglia,
DC, CD8+ CTL, CD4+ Teff, and Tregs). Based on this finding, a
TAMC-targeting lipid-based nanoscale system with surface-
modification by aPD-L1 and encapsulation of dinaciclib (a
cyclin-dependent kinase 5 inhibitor) was developed to treat
TAMCs. Specifically, flow cytometric analysis confirmed that via
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the Rhod-PE-labelled approach, aPD-L1-LNP exhibited a high
efficiency in targeting in vitro-generated TAMCs, as well as
human-derived TAMCs, which were isolated from the periph-
eral blood and tumor tissue of glioblastoma patients. In addi-
tion, the viabilities and immunosuppressive activities of
TAMCs were effectively impaired by this aPD-L1-LNP. Further-
more, thanks to the effective scavenging of TAMCs to prevent
an increase in their PD-L1 level after RT, the combination of RT
with aPD-L1-LNP effectively extended the survival time of two
syngeneic gliomas models of GL261 and CT2A compared to that
treated with RT.408
Polarizing tumor-associated macrophages. Polarizing pro-
tumor M2-like TAMs to the pro-inflammatory ones is another
promising approach to overcoming immunosuppression.
Immunomodulatory agents, such as NO donor S-nitrosothiol,
anti-CD40, toll-like receptor agonists (resiquimod or imiqui-
mod), bexarotene, chlorogenic acid, and TMP195, have been
reported to aid in this transformation process.409–412 For
instance, it has been reported that lipidic polyplex-aided deliv-
ery of the plasmid of IL12, a pro-inflammatory chemokine,
could increase the ratio of M1/M2 by more than four times.413
Moreover, Ginseng-derived nanoparticles (GDNPs), isolated
from Panax ginseng C.A. Mey, were found to polarize TAMs to
the M1-like one via the TLR-4/myeloid differentiation antigen
88 signaling pathway.414
Specifically, b-alanine-modified Gd@C82 (GF-Ala) nano-
particles were reported to re-educate TAMs to a tumoricidal
M1-like phenotype through the activation of NF-kB and IRF5
pathways. This fabricated GF-Ala nanomedicine had an average
diameter of 68.1  2.3 nm and a negative surface potential of
37.7  0.3 mV. After treatment of RAW264.7 cells with the
nanomedicine, the expression of TNF-a, a classical M1 marker,
was sharply increased over 3.6 times than that in the untreated
RAW264.7 cells. Meanwhile, the level of IL-10, a classic M2-
related maker, was 32.6% lower in the GF-Ala-treated group
than that in control cells without any treatment. The nanome-
dicine in combination with anti-PD-L1 to treat a 4T1
tumor model exhibited a pronounced synergistic antitumor
effect. Given the radio-sensitization properties of high-Z
gadolinium, its antitumor effect could be further improved
with the intervention of RT (Fig. 12b).172 In another report, a
metallic radiosensitizer-assisted radio-immunotherapy (exter-
nal RT + anti-PD-1) was developed and effectively reduced the
percentage of M2-like macrophages. L-Glutathione-modified
triangle-shaped tellurium nanostars were prepared via a
shape-control one-pot hydrothermal method. Their following
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surface-decoration with a targeting ligand, RGD (Arg–Gly–Asp),
and biocompatible chitosan constituted a radiation-driven
immunotherapeutic enhancer, GTe-RGD. In vitro experiments
demonstrated that GTe-RGD could improve the radiation sen-
sitization of tumor cells including A375, HeLa, and 4T1 cells.
GTe-RGD exhibited GSH-responsive degradability, promoting
its in vivo clearance after its therapeutic function. Furthermore,
the percentage of the M2 phenotype was much lower in the
tumor tissue and slightly lower in the spleen tissue in the 4T1
breast murine mice group treated with GTe-RGD + X-rays/anti-
PD-1 than that in the groups receiving PBS, GTe-RGD, X-rays,
and GTe-RGD + X-rays (Fig. 12c).406 Additionally, the joint use
of hydrophobic imiquimod and hydrophilic aCD47 co-
delivered by an Hf-DBP nMOF exerted a TAM repolarization
effect in bilateral CT26 tumor models. In this study, imiqui-
mod, a TLR-7 agonist, was loaded in the pore of the MOF and
aCD47 was attached onto the surface of the Hf-DBP nMOF with
acetate capping groups. In contrast to the PBS-treated group,
this nanomedicine-mediated treatment increased the M1 popu-
lation by 7.6% and reduced the M2 population by 15.7%. When
the nanomedicine was further combined with RT, a nearly one-
fold increase and drop was observed in the percentage of M1
and M2 cells, respectively.415
Disturbing immunosuppression-related pathways and immuno-
suppressive agents. In cancer sites, such as liver metastasis sites,
TAMs, MDSCs, Kupffer cells, and hepatic dendritic cells collec-
tively form and support a network of active immunosuppressive
pathways, suppressing the activation of CD8+ effector and CD4+ T
cells and inducing immune tolerance to immunotherapy.396,416,417
In addition, an increase in the level of TNFa and TGF-b induced
by RT, and the rapid formation of adenosine from ATP released by
RT could be the culprits of immunosuppressive agent-mediated
immune tolerance.418–420 In detail, RT-induced TGF-b exerts
multiple immune-suppressive activities, such as suppressing
effector T cells, promoting tumoral infiltration of Tregs, and
driving DCs to the immune-tolerogenic phenotypes.421 To con-
clude, these immunosuppression-related signaling pathways and
immunosuppressive agents could be harnessed to overcome
resistance to immuno-oncology-associated treatments.
Specifically, it has been reported that the inhibition of the
BTK-PI3Kg signaling pathway and blocking the CD47-
SIRPa axis contribute to reverse immunosuppression.422
Furthermore, the blockade of the CCL2/CCR2, CXCR4-
CXCL12, CSF-1/CSF-1R signaling pathways effectively prevented
macrophage infiltration in the tumor, and the inhibition of
CSF-1R in macrophages promoted therapeutic antibody-
dependent phagocytosis of cancer cells.423–426 For example, a
synthetic protein nanoparticle, comprising human serum albu-
min, fluorescently-labelled bovine serum albumin, iRGD,
AMD3100 (a CXCR4 antagonist), and bifunctional macromer,
has been shown to block the CXCR4-CXCL12 pathway in the
orthotopic genetically engineered glioblastoma murine models.
Furthermore, its combination with RT (2 Gy  10 fractions)
promoted an extended survival time. Three mice survived over
60 days, while all the mice in other treated groups were dead.426
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Overall, despite a small number of studies on the use of
nanomedicines to intervene immunosuppression-related sig-
naling pathways and immunosuppressive agents,420,426 inhibi-
tors for these pathways and agents can be incorporated into
nanocarriers for overcoming immunosuppression, improving
their solubility and bioavailability while reducing their toxicity
induced from their accumulation in the normal tissue.
4.5 Remission of the therapy-induced toxicity issue
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Nonspecific deposition of high radiation energy and distribu-
tion of immuno-oncology agents during cancer radio-
immunotherapy are the primary toxicity-inducing factors. RT-
induced acute and late-onset adverse events include brain
damage (edema, radionecrosis, neurocognitive impairment,
and brain inflammation), lung injury (pneumonitis and fibro-
genesis), and lymphotoxicity.427 These adverse events have
been reported to be associated with the cGAS-STING signaling
pathway,428 while the toxicities from the immuno-oncology
treatment depend on immunotherapeutic drugs. The use of
ICIs is often accompanied by multi-organ inflammation
(derma, gastrointestinal, and endocrine),429,430 while CAR T
cell therapy and cytokine therapy may lead to the cytokine
release syndrome and/or the immune effector cell-associated
neurotoxicity syndrome.431
From the above discussions, it can be seen that the adverse
events induced by RT and immunotherapy are strongly related
to inflammation. High-dose steroid therapy can effectively
relieve the severity of inflammation. However, steroid-
refractory irAEs, such as nonendocrine irAEs, are insensitive
to this therapy.432 Therefore, protective drugs, detoxicant
agents, or other strategies to reduce radio- or immuno-related
toxicities have been explored. A couple of agents, including
memantine, selenium, and anti-CD47 antibody, confer a radio-
protective effect to the brain tissue undergoing whole-brain
radiotherapy and the adjacent normal tissues predominantly
via a ROS-scavenging manner.433–435 Meanwhile, masking
agents or antibody-clearance agents are dedicated to relieving
immune-associated toxicity.
Radiation proctopathy (RP) is the result of inflammation of
the colorectal tissue after RT, in which the platelet-derived
growth factor C (PDGF-C) and excessive ROS can act as ther-
apeutic targets.436 In one study, upregulation of PDGF-C was
found in the tissues with RP either from patients or animal
models and genetic deletion of PDGF-C in mice could relieve
RP-associated adverse effects. In their following experiments,
the use of crenolanib, a selective agonist for PDGF receptors, in
a PEG-400-based solubilizer, successfully prevented and/or
ameliorated RP in mice, supported with a 20% thickness
reduction of the submucosal layer and a decreased level of
expression of fibrosis markers (a-SMA and fibronectin) in a
mice model 8 weeks after RT.437 Another study employed
spherical polydopamine nanoparticles (PDA-NPs) at 50 mg
kg1 via an oral administration route to scavenge ROS and
suppress inflammation in RT-induced intestinal injury murine
models. Successfully, the content of MDA, an indicator of
the lipid peroxidation of intestines, was reduced by B3 fold
Chem. Soc. Rev.
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or B1 fold in RT + PDA-NPs on day 1 or day 3.5 post-radiation,
respectively, compared to that with radiation only. Moreover,
from immunohistochemical assays and fluorescence imaging,
the PDA-NPs + RT-treated mice group exhibited superior
protection of intestinal-associated cells (Lgr5+ intestinal
stem cells, lysozyme+ Paneth cells, ki67+ crypt base columnar
cells, or villus+ intestinal cells length) than the radiation-only
group.266
The application of customized masking agents to develop
immunotherapeutic prodrugs for switchable immune modula-
tion is another example of using nanomedicines to realize
tumor-specific activation of antitumor immune response and
prevention of undesirable normal tissue accumulation.438 Engi-
neering interleukin-based prodrugs is a preferable method to
reduce immune-toxicity without compromising their therapeu-
tic efficiency. For instance, an IL-2 mutein/Fc fusion protein, a
biological binding site for CD8 T cells, was masked with an IL-2
receptor via a matrix metalloproteinase (MMP)-cleavable linker.
Similarly, a recent study employed the masking strategy to
reduce the immunotoxicity of IL-12. They fused a domain of
the IL-12 receptor to IL-2 via a MMP-responsive linker.96 There-
fore, the masking strategy via nano-engineering protease-
sensitive linkers significantly reduces the toxicity in cytokine-
based immunotherapy, meanwhile, the specific-site drug dis-
tribution and the antitumor effect have been greatly improved.
In addition, a significant shortcoming of current antibody-
based immunotherapy is their excessive blood circulation time,
which may lead to the formation of thrombus and other
adverse effects. These adverse effects and their immunogenic
properties may cause damage to healthy tissues after the
administration of these antibodies. Nanosized click antidotes,
avidin chases, and other nano-agents have been employed for
blood clearance of antibodies or nanomedicine-mediated stra-
tegies have emerged to accelerate blood clearance of these
antibodies (Fig. 13).219,439–442
Overall, a few toxicity-inducing mechanisms of cancer radio-
immunotherapy are well-studied, while the majority of them
are still unknown. Improved biodistribution and pleiotropic
immunomodulatory effects of nanomedicines, as well as
employment of specific radio- or immune-protective drugs,
can help in addressing issues of already identified toxicities.
Non-specific body retention of nanomedicines should be
reduced for their long-term safety. Renal- or hepato-clearance
strategies have been applied to the design of these nanomedi-
cines. Quantitative structure–activity relationships of the nano-
medicines could be examined to reduce their toxicities. More
importantly, toxicity from the common composition of nano-
medicines should be seriously considered. Take PEG for exam-
ple, the PEGylated approach can greatly alleviate the systemic
toxicity of IL-2 (extensive inflammation and a fatal vascular leak
syndrome), a cytokine used in adoptive cell transfer for T-cell
expansion in clinical practice, which originates from non-
specific distribution of IL-2 receptors.443 According to a recent
report, PEGylated liposomes containing TLR agonists induced
hypersensitivity reaction upon multiple dosing, which may be
attributed to the generation of anti-PEG IgGs.444
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Fig. 13 Scheme for emerging nanomedicine-mediated strategies to accelerate blood clearance of antibodies. Various scavenging nano-agents have
been designed to combine excessive engineered antibodies in the blood stream for rapid clearance via five main strategies, including tco-tetrazine,
azides-cyclooctynes, complementary DNA, biotin–streptavidin, and bsAbs-haptens. Ref. 219 and 439–442.
5. Considerations for clinical
translation and future directions
Clinical translation of nanomedicine-mediated radio-
immunotherapy will benefit more cancer patients. However,
numerous factors need to be carefully considered before these
nanomedicines enter clinical trials. We will summarize the
challenges in this field, discuss lessons learned from ongoing
or completed clinical trials on radio-immunotherapy, and
provide insights into challenges and future research direction
of this combined therapeutic methods.445–448
5.1 Summary of the challenging issues for radio-
immunotherapy
In the past five years, a myriad of nanoformulations have been
explored for radio-immunotherapy. This nanotechnology-aided
therapy, mostly in the preclinical stage, helps in addressing a
low response rate and systemic toxicity, as well as realizing
therapeutic benefits, including effective systemic tumor control
and long-term immune memory protection. However, chal-
lenges remain in the current trials of nanomedicines for
radio-immunotherapy. Three prominent challenges are
highlighted below.
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(i) Current nanoscale delivery systems are complex. Excess-
engineering of the chemical structure and equipping with many
functional moieties are often sought in the preparation of nano-
medicines for realizing radio-immunotherapy. The primary con-
cern of these nanomedicines is the reproducibility during their
preparation process. Furthermore, the interaction between nano-
formulations (e.g., PEGylated nanomedicines) and biological
organs/tissues/cells still largely remains unknown.449 In particular,
great efforts are needed to discover the interaction between these
nanomedicines with a complex structure and the systemic immu-
nity in the patient. More importantly, incorporation of multiple
biological active agents in one single nanoplatform may increase
the complexity of unveiling their synergistic mechanisms of
action. Thorough investigations of a single promising active agent
in the nanomedicine should be conducted to reveal its working
mechanisms and additional active agents could be expanded to
realize synergistic therapeutic benefits. In this context, MnO2 NPs
may be a great candidate for radio-immunotherapy of cancer.
MnO2 nanomedicine-mediated immunomodulation and radio-
sensitization have been discovered to some extent: Mn2+ aug-
ments the STING signaling and hypoxia-mediated radioresistance
is relieved by oxygen generation in a MnO2-mimic catalyst decom-
position of over-expressing H2O2 in TME.116
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(ii) There are too many combinational treatment options.
Many factors could play a role in the application of the
nanomedicine as a mono-therapeutic agent for radio-
immunotherapy or an adjuvant to RT and immunotherapy.
These factors include administration routes, sequence, admin-
istration intervals, radiation doses, fractionation, the radiation
source, and doses of the therapeutic agent(s) and the nanocar-
rier. Consequently, superfluous treatment plans could be for-
mulated from the combination of the above factors, but these
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plans for a nanoformulation could not be fully executed con-
sidering the experimental cost and resources. It is advised to
narrow down these factors based on previous and ongoing
clinical trials and practice. In view of the complex radiation-
immunity net, we suggest establishing a radiation dose and
fractions for one indication. Robust immunity-eliciting radia-
tion schemes (e.g., 8 Gy  3 fractions) have been applied to
compare the synergistic effects of various immunomodulatory
nanoagents.52 Meanwhile, a hypofractionated low-dose radia-
tion plan (e.g., 2 Gy  5 fractions) is combined with one
immune-drug, such as an ICI, to compare radiosensitivity and
the synergistic abscopal effect of different metal or non-metal
radiosensitizers.450,451 Additionally, the initial tumor volume,
administration frequency, dosing, administration route, and
therapeutic sequence could be standardized to establish the
evaluation criteria for these nanomedicines.
(iii) Complete profiles of the immunogenicity and immuno-
toxicity of nanocarriers need to be established. The immuno-
toxicity of PEGylated liposomes used as a vaccine was recently
revealed,452,453 including the anti-PEG IgG-induced hypersensi-
tivity reaction.444 However, there are very few reports on thor-
ough characterization of immunogenicity and immunotoxicity
of polymer-, protein-, or inorganic-based nanocarriers. The
standardized characterization methods should be established
to accelerate the translation of nanomedicines for clinical
trials. Recently, polysaccharides,454 cell membranes of treated
tumor or immune cells,455,456 and bacterial outer membranes
are pursued as personalized nanocarriers because they can
elicit robust adaptive and innate immune response.457 The
immunogenicity and immunotoxicity of these personalized
nanocarriers are two of the most critical quality attributes
(CQAs). The impurities in the preparation of these nanocar-
riers, such as endotoxin and chemical residuals, may also
induce innate immune response, which could provide an
inaccurate profile of immunogenicity and immunotoxicity of
personalized nanocarriers.
5.2 Lessons learned from ongoing clinical trials
Over 500 clinical trials have been registered in the NCT data-
base (https://clinicaltrial.gov/ct2/home) on cancer radio-
immunotherapy during the past five years. Although there are
a very few trials on nanomedicine-assisted radio-immuno-
therapy, the number of trials has been steadily increasing due
to unique advantages and attributes of these nanomedicines as
well as an increase in the approval of nanomedicines for other
therapies. Strengths and weaknesses of these clinical trials
could provide great insights into effective clinical translation
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of this nanomedicine-assisted combined therapy. Particularly,
lessons from the the terminated, withdrawn, or suspended
trials can help in designing and preparing nanomedicines,
building patient cancer-mimicking animal models, and formu-
lating treatment procedures for this radio immunotherapy. We
have listed a few lessons from these trials.
(i) Recruitment of inadequate patients for trials. A high risk
of a new treatment may deter patients from participating these
trials. Some of the enrollment criteria are set too high and very
few patients can meet the enrollment criteria. A clinical trial
screening tool to analyze 16 095 potential participants revealed
that 13% of them did not enroll into the trial because they did
not meet the trial eligibility.458 Solid preclinical data should be
obtained to provide consistent and efficacious treatment in
animal models. The clinical benefits of this treatment should
be easily understood by these patients.
(ii) Poor or slow accrual. Many clinical trials are terminated
or suspended due to poor or slow accrual. An unoptimized trial
protocol, chronic and acute comorbidities (e.g., hypertension or
diabetes) of participants, a low recruitment momentum, a slow
screening process for the first trial participants, and a better
alternative therapy may result in poor or slow accrual.459
(iii) Insufficient supply of nanomedicines. For instance,
CCX872-B, a CCR2 inhibitor, was in shortage in a phase I/II
trial (NCT03778879). Challenging issues with chemistry, man-
ufacturing and control (CMC) of nanomedicines, a high man-
ufacture cost, or an insufficient manufacturing capacity could
contribute to inadequate supply of nanomedicines for clinical
trials. Facile preparation of nanomedicines with simple chem-
istry or structures could be readily transferred to large-scale
production. Great reproducibility, a high yield in a large scale, a
high purity of pharmaceutic active ingredients, and fewer
preparation steps are essential for the CMC of these nanome-
dicines in good manufacturing practice (GMP). Importantly,
CQAs of nanomedicines in terms of potency and safety should
be thoroughly studied.
(iv) Ineffective treatment and high toxicity. A low biological
efficacy and CD19 CAR CTL persistence result in terminating a
phase I/II trial (NCT01195480). A tumor lysate vaccine, Imiqui-
mod, and RT were used in another phase I trial (NCT01400672)
to treat diffuse intrinsic pontine glioma and glioblastoma
multiforme and this trial terminated due to ineffective treat-
ment and high toxicity.
Overall, many factors contribute to the successful clinical
translation of a nanomedicine to a specific indication. Treat-
ment effectiveness and tolerant toxicity are two critical factors.
Currently, there are few clinical trials in nanomedicine-
mediated radio-immunotherapy. An approach to combining
clinically used radiation therapeutic methods and approved
immunotherapeutic nanoformulation agents should be consid-
ered for nanomedicine-mediated radio-immunotherapy first,
and this approach can accelerate the clinical translation of this
new treatment and the ensuing other nanomedicine-assisted
radio-immunotherapy. In addition, feasible and precise cri-
teria, along with reliable nanomedicine-aided imaging meth-
ods to differentiate the disparity in the treatment response and
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predict the degree of toxic, adverse effects have not been
established due to the slow response of immunotherapy and
radiotherapy.
5.3 Challenges for clinical translation
Despite the inspiring results from preclinical studies and a few
clinical trials, there are many challenges for clinical translation
of the nanomedicines in radio-immunotherapy.
Generally, good manufacturing practice (GMP), gram or
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kilogram-scale production, and facile, reproducible prepara-
tion procedures are the three major hurdles on the way of
nanomedicines’ ‘‘from bench to clinic’’.460,461 In the context of
nanomedicine-mediated cancer radio-immunotherapy, there
are other specific issues.
(i) Challenges in building in vitro cell assays. Since the
combinational biological basis of radiotherapy and immu-
notherapy is in a systemic manner, conventional in vitro cell
assays fail to evaluate their therapeutic efficacy. Establishment
of specifically designed cellular assays is always time- and
resource-consuming. For instance, the main procedure of the
in vitro cross-presentation assay usually takes 1–2 weeks to
complete, and this does not include the duration for isolating
and stimulating bone marrow-derived dendritic cells and CD8+
T cells from the murine bone marrow or spleen.462
(ii) Lack of investigation of large-scale human tumor-derived
samples in animal models. Due to the inherent limitation,
murine cell lines are often employed for most pre-clinical
studies in radio-immunotherapy. A few humanized murine
models still experience issues, such as rejection, poor or low
MHC-restricting antigen-specific immune response, and a
complex modeling process, thus hampering their wide
application.463,464 So far, there is a lack of large-scale studies
on human tumor-derived cell lines or tissues or organoids in
animal models. Effective humanized murine models could help
in shortening the gap between preclinical studies and clinical
trials or practices.
(iii) Simple design and facile preparation of nanomedicines.
Several adjuvant agents or pharmaceutical preparations for
cancer vaccines and inorganic radiosensitizers have undergone
clinical trials.175,465,466 Their chemical structure is simple and
their prepare process is readily implemented in a GMP environ-
ment, thus their pharmacokinetics, therapeutic efficacy, safety,
and tolerability can be monitored or evaluated via currently
established methods.
To conclude, this research area is still in its fetal period and
its great potential remains to be explored. Great efforts need to
be devoted to this research area. Currently, over-engineered
nanomedicines in a controlled manner could provide a
potential means of accelerating their clinical translation for
simultaneously exploring the biological function and synergis-
tic biological effect of multiple agents. After the mechanistic
action of these over-engineered nanomedicines is revealed,
their structure and preparation could be simplified. More
importantly, personalized treatment in this emerging research
field, consisting of nanotechnology-aided modification and
optimized CAR T cells, DCs, tumor cells, or antigenic tumoral
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peptides obtained from patients’ biological samples, involves
superfluous less controllable steps and has reproducible issues,
but increasing evidence from these preclinical studies or clin-
ical trials contribute to developing potent, simple, personalized
nanomedicines.467,468
5.4 Future directions
Based on the challenging issues, lessons drawn from ongoing,
completed, or withdrawn trials, along with recent advances in
this field, we suggest three promising research topics on
nanomedicine-assisted cancer radio-immunotherapy: radiola-
belled immunogenic antibodies for theranostics, harnessing inflam-
mation, and metastases-directed combined therapy.
Radiolabeled, immunogenic antibodies for theranostics.
Introducing theranostic radionuclide pairs into the antibodies
with immunological regulation effects, such as ICIs, non-
Hodgkin lymphoma-treating monoclonal antibody (mAb) (Bex-
xar and Zevalin), bispecific mAbs, and mAb conjugates,469
could achieve precise SPECT/PET-assisted radio-immuno-
therapy. These radiolabeled antibodies may amplify antitumor
immune response by simultaneously revitalizing effector T
cells, reprogramming the immunosuppressive tumor stroma,
and monitoring and killing tumor cells. One concern over this
novel treatment lies in that the energy emitted from the loaded
radionuclides may affect the inherent function of antibodies. It
has been demonstrated in previous studies that the function of
mAbs was not compromised after the addition of diagnostic
radionuclides (32P or 131I) to anti-PD-1 or anti-PD-L1
mAbs.382,470 However, since therapeutic radionuclides generate
relatively high radiation energy than diagnostic ones, low-dose
therapeutic radionuclides could be selected to regulate the
tumor immunological microenvironment. This issue deserves
more efforts for preparing clinically-translatable radiolabeled,
immunogenic antibodies.
Additionally, expanding the repertoire of theranostic radio-
nuclides can be critical for this treatment method. Visible
isotopes of currently used therapeutic radionuclides may be
such a candidate. For instance, thyroid tumor ablation was
realized with the help of 131I, and liver cancer with 90Y micro-
spheres. Their corresponding isotopes, such as 124I and 86Y,
could be utilized to achieve imaging function.471 Other typical
theranostic pairs include 64Cu/67Cu, 68Ga/67Ga, 83Sr/89Sr,
203
Pb/212Pb, and 72As/77As.472 Their radioactive potencies and
biological half-lives should be considered during the selection
of these theranostic pairs: the half-lives should be slightly long
enough to cover the duration including customized labelling,
average cargo delivery, and peak tumor accumulation; and after
adequate tumoral accumulation they can exert their tumor-
killing effect in a rational time range without noticeable
adverse effects. Chelator binding prevails in the current radi-
olabeling methods.473 In addition to clinically used chelators,
such as 1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA)
and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), other
tightly-bound and selective chelating ligands with high specific
activities could be explored. Moreover, tumor-specific targeting
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moieties of these ligands should be modified to avoid potential
damage to immune cells.
Harnessing inflammation. Prolonged inflammation, a hall-
mark of cancer, is closely correlated with excessive ROS-
induced oxidative stress and it may account for tumor progres-
sion since an elevated ROS level in the TME may weaken ICD
and tumoral infiltration of CTL cells.474,475 Cancer treatment
methods, such as radiation therapy and immunotherapy, can
also induce inflammation, and a key step of inducing inflam-
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mation is the vascular reaction.
The inflammation process originating from RT may have
‘‘double-sword’’ impacts on cancer immunity. On the one hand,
RT induces rapid inflammatory response via recruiting TAMs,
leading to pseudo-progression and hindrance of timely and
effective treatment.476 Furthermore, immune analysis reveals that
incomplete radiofrequency ablation induces sustained local
inflammation with predominant myeloid suppressor cells, which
inhibit T cell function in tumors.477 On the other hand, RT-
induced inflammation contributes to shaping the antigenicity of
tumor cells, as well as the phenotype, immune-polarity, and
density of inflammatory immune cells.476
Notably, inflammation can be a therapeutic target.478,479
Therapeutic intervention of chronic inflammation in tumors
could enhance the clinical efficacy of therapeutic vaccines and
adoptive T cells,480 because inflammation in the tumor can
lead to caspase-1-dependent pyroptosis, a highly inflammatory
form of programmed cell death.481,482 On basis of this finding,
a few nanomedicines have been designed to augment inflam-
mation. For example, the phospholipid-coated Na2S2O8 NP, an
H2O2-independent ROS-generating agent, was in situ degraded
to toxic  SO4 and  OH. The osmotic pressure induced by
excess released Na+ from this peroxydisulfate NP led to
caspase-1 dependent pyroptosis, evidenced by a significant
increase in the caspase-1 activity and secretion of IL-1b in
4T1 and CT26 cells treated with this NP.483
Overall, inflammation could be harnessed during radio-
immunotherapy of cancer. The inflammatory TME could be
remodeled via RT, and anti-inflammation drugs are then used
to avoid adverse events. However, the antitumor inflammatory
effect is in a transient therapeutic window and anti-
inflammation drugs should be administered to avoid long-
term inflammation and inflammation-induced toxicity. A
highly efficient indicator for the therapeutic window is to be
established for maximizing the positive effect of therapy-
inducing inflammation but minimizing its adverse effects.
Metastasis-directed combined therapy. Metastases are the
primary culprit of high mortality in cancer patients. After
migrating to the secondary or more distant sites, plastic metas-
tasizing tumor cells can colonize and modulate the local
environment. A dormancy site that is insensitive to therapeutic
interventions can be thereafter formed.484 It has been reported
that oligo-metastasis with 3–5 metastasis sites has been shown
to gain distinctive clinical benefits by combined radio-
immunotherapy.485,486
Nanomedicine-mediated radio-immunotherapy could be
potent to this deadly indication, and it could detain growth,
Chem. Soc. Rev.
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regression, or recurrence of both primary and distant
tumors.487,488 In a recent report, phosphatidylserine-coated
liposomes loaded with cyclic guanosine monophosphate-
adenosine monophosphate, NP-cGAMP, were aerosolized for
inhalation administration to treat multifocal lung metastases
in combination with fractionated RT (24 Gy/3 fractions). Phy-
siochemically, this NP-cGAMP had a size of around 119 nm and
a zeta potential of 41 mV. Two distinctive in vivo lung
metastasis models were built through intravenously injected
B16-OVA cells and orthotopically injected 4T1-Luc cells into
mammary fat pads. Lung metastasis sites were significantly
reduced in both tumor models after the combined treatment of
NP-cGAMP and RT compared to other therapies. Monitoring of
4T1 lung metastases with 39 day IVIS and MRI revealed that the
metastasis sites after this treatment were under well control
and the ratio of CD8+ T/Treg in 4T1 lung metastases was
improved.489
Currently, a CREKA (Cys–Arg–Glu–Lys–Ala) peptide, target-
ing fibrin–fibronectin complexes in the tumor stroma and
vessel walls, has been widely used as a metastasis-specific
ligand.490 After more therapeutic targets for metastases, includ-
ing melanocortin 1 receptor for metastatic melanoma and
leucine-rich alpha-2-glycoprotein 1,491,492 have been discovered
and confirmed, other reliable and feasible targeting ligands can
be thereafter designed and applied to modify nanomedicines
for treating multiple metastases, especially the tiny one. In
addition, tumor metabolism can be exploited as a potential
target to halt tumor cell growth and prevent tumor seeding
since a few metabolic pathways experience dynamic changes
during tumor migration.493
6. Conclusions
A body of evidence from preclinical studies and clinical trials has
indicated that cancer radio-immunotherapy has distinctive advan-
tages over monotherapy in improving therapeutic outcomes and
mitigating immune- or radio-induced toxicity. Furthermore,
unique properties of nanomedicines, such as tumor/lymphatic
system-specific targeting, radio-sensitization, accommodation of
multiple immunomodulators, and size/shape/surface tunability,
endow them with multiple indispensable and supplementary
roles in this synergistic radio-immunotherapy. Among these roles,
nanomedicine-mediated imaging could help in the differentiation
of the tumor immune state, patient stratification, diagnosis,
monitoring and timely assessment of therapeutic response and
prediction of long-term clinical benefits. In addition, amplifying
the tumoricidal effect and reducing therapy-induced toxicities to a
tolerant level have been achieved through rational design of
nanomedicines with flexible modification in overcoming therapy
resistance, eliciting solid innate or adaptive immune response,
reinvigorating cytotoxic effectors, and increasing immune-
metabolic interplays.
Although the working principles of synergistic radio-
immunotherapy and mechanisms of reversing immune- and/
or radio-suppression have been unveiled to some extent for the
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Chem Soc Rev
nanomedicines in animal models, there are many challenges in
the transitional process of ‘‘from bench to clinic’’ for nanome-
dicines in radio-immunotherapy. A consortium convened from
multi-disciplinary teams could be formed to establish the
criteria for therapeutic response, clinical benefits, acceptable
toxicity level, patient selection and the library of suitable
nanomedicine candidates for cancer radio-immunotherapy.
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Author contributions
H.-N. Li, Q. Luo, and K. Luo conceived the outline of this
review. H.-N. Li and Q. Luo collected papers for writing. H.-N. Li
drafted the manuscript and performed the creation of figures.
H. Zhang, X.-L. Ma, and Z.-W. Gu helped revise the manuscript
and discuss the content. Q.-Y. Gong and K. Luo supervised this
project and finalized this manuscript.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Fig. 1–5, 7b(i), 8, 10 and 13 and table of contents entry were
created with BioRender.com. This work was financially sup-
ported by the National Natural Science Foundation of China
(52073193, 51873120, 81621003), 135 project for disciplines
of excellence, West China Hospital, Sichuan University
(ZYJC21013).
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