Biomaterials 282 (2022) 121433

Contents lists available at ScienceDirect

Biomaterials
journal homepage: www.elsevier.com/locate/biomaterials

Emerging photodynamic nanotherapeutics for inducing immunogenic cell

death and potentiating cancer immunotherapy
Shenwu Zhang, Jing Wang, Zhiqiang Kong, Xinxin Sun, Zhonggui He, Bingjun Sun **,
Cong Luo ***, Jin Sun *
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, PR China

A R T I C L E I N F O A B S T R A C T

Keywords: Immunotherapy has emerged as a promising cancer treatment modality. Despite the rapid progress in cancer
Photodynamic therapy immunotherapy, the therapeutic efficiency and clinical translation of immunotherapy are not as satisfactory as
Nanotherapeutics expected, especially for the patients with immune-cold tumors. Immunogenic cell death (ICD) represents a
Immunogenic cell death
particular form of tumor cell death accompanied by the production of tumor-specific antigens, which facilitates
Synergistic induction
Cancer immunotherapy
the infiltration of effector T cells and potentiates immune response in solid tumors. Thus, ICD contributes to
stimulating immune-cold tumors to immune-hot ones. Increasing evidence shows that photodynamic therapy
(PDT) is able to effectively induce ICD. Recently, a variety of photodynamic nanotherapeutics have been
developed to induce ICD and to potentiate cancer immunotherapy. Herein, this review outlines the recent ad­
vances in the field at the intersection of PDT, nanotechnology and ICD, including PDT-induced ICD, PDT-based
synergistic induction of ICD, and multimodal immunotherapy in basis of PDT-induced ICD. Finally, the prospects
and challenges of these photodynamic nanotherapeutics in ICD induction-based cancer immunotherapy are
discussed.

1. Introduction immune response, resulting in unsatisfactory immunotherapeutic effi­

Malignant tumors remain a severe threat to human health [1]. In
recent years, immunotherapy has shown promising application pros­
pects in clinical practice [2–9]. Compared with traditional treatment
strategies, the emerging immunotherapy not only suppresses the growth
of primary tumors, but also effectively prevents the metastasis and
relapse of tumor by harnessing the inherent immune system of patients
[10,11]. Typical immunotherapy strategies mainly include nonspecific
immunostimulation, immune checkpoint-blockade (ICB) therapy, tumor
vaccine, adoptive cellular immunotherapy (ACI) [12,13]. Among them,
immune checkpoint programmed death 1 (PD-1)/programmed
death-ligand 1 (PD-L1) pathway blockade has been discovered as a po­
tential immunotherapy modality [14,15]. Notably, PD-1/PD-L1
blockade immunotherapy heavily depends on the full infiltration of
activated T lymphocytes into tumor tissues. Nevertheless, a considerable
proportion of the clinical patients with immune-cold tumors exhibit low
cacy [16–18]. Therefore, how to promote the transformation of
immune-cold tumors to immune-hot ones could be of crucial signifi­
cance for efficient immunotherapy.
In recent decades, it has always been believed that immune re­
sponses could only be triggered by exogenous substances. But in late
1990s, studies showed that endogenous entities could also evoke im­
mune responses under certain conditions [19]. In 2005, Kepp et al.
firstly demonstrated that tumor cells exposed to doxorubicin (Dox) were
capable of acting as vaccine and activating host immunity during
apoptosis, and named this form of cell death as immunogenic cell death
(ICD) [20,21]. Since the concept of ICD was first proposed in 2005, host
immunity has received considerable attention in cancer treatment [22].
The emergence of ICD and ICD-based synergistic therapeutics has
bridged the gap between traditional and new treatment modalities [23].
Particularly, ICD induced by traditional therapies has emerged as a
promising strategy to convert immune-cold tumors to immune-hot ones

* Corresponding author.
** Corresponding author. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016,
China.
*** Corresponding author.
E-mail addresses: sunbingjun_spy@sina.com (B. Sun), luocong@syphu.edu.cn (C. Luo), sunjin@syphu.edu.cn (J. Sun).

https://doi.org/10.1016/j.biomaterials.2022.121433
Received 14 October 2021; Received in revised form 21 January 2022; Accepted 17 February 2022
Available online 19 February 2022
0142-9612/© 2022 Elsevier Ltd. All rights reserved.
S. Zhang et al. Biomaterials 282 (2022) 121433

in tumor immunotherapy (Fig. 1) [24–27]. After the induction of ICD,

the dying tumor cells release tumor associated antigens (TAAs),
pro-inflammatory cytokines and danger associated molecular patterns
(DAMPs) [27,28], such as heat shock proteins (HSPs) [29], calreticulin
(CRT) [30–33], high mobility group box 1 (HMGB1) [33,34], and
adenosine triphosphate (ATP) [35,36]. The released DAMPs can stim­
ulate the maturation of dendritic cells (DCs), and subsequently the
mature DCs carrying cancer-specific antigens migrate to the lymph
nodes, activating effector T cells [37]. Finally, the activated effector T
cells migrate and infiltrate into tumor tissues to eliminate tumor cells
[37].
Given that ICD is induced via apoptosis in most cases, it is usually
themed as immunogenic apoptosis. Recently, several nonapoptotic cell
death modalities have also been found to be related to antitumor im­
munity [38]. For instance, necroptosis is a modality of programmed cell
death along with the release of intracellular contents amongst DAMPs,
Fig. 2. Schematic representation of photodynamic reactions.
which evokes antitumor immunity through activation of nuclear
factor-κB (NF-κB) or priming and activation of effector T cells [39,40].
Moreover, ferroptosis has also emerged as a new cell death modality half-life of most PSs, the tumor hypoxic microenvironment, and the
induced by iron ion-mediated accumulation of lipid peroxides [41]. It insufficient accumulation of ROS in ER hampers the induction of ICD
has been found that tumor cells undergoing ferroptosis can release [48,49]. In addition, there are still some inherent limitations of PDT that
HMGB1 by autophagy [42]. In turn, the infiltration of CD8+ T cells can are not sufficient to evoke a strong immune response. Moreover,
facilitate and enhance the occurrence of tumor ferroptosis [43]. Actu­ single-modal cancer immunotherapy based on PDT-driven ICD is not
ally, immunogenic cell death refers to an umbrella term, some other cell enough to attain a satisfactory therapy outcome. Therefore, it’s neces­
death modalities such as necroptosis and ferroptosis were also found sary to improve the in vivo delivery efficiency of PSs and design com­
with immunogenic features [38]. However, the detailed mechanisms of bined therapeutic strategies for efficient PDT-driven immunotherapy.
antitumor immunity induced by these nonapoptotic cell death modal­ With the burgeoning of biomaterials engineering and nanotech­
ities still remain not entirely clear. nology, nanoparticulate drug delivery system (nano-DDS) has been
Several conventional treatment modalities have been found to cause widely investigated as an efficient platform for the delivery of anticancer
tumor cell death in an immunogenic way, such as chemotherapy, drugs [50–54]. Among them, a wide range of photodynamic nano­
radiotherapy, and photodynamic therapy (PDT). Among them, PDT, as a therapeutics have been developed for cancer treatment [55–57].
non-invasive therapeutic modality, has been widely investigated for Formulating PSs into nanocarriers could offer many advantages, such as
localized cancer therapy [44–46]. Under localized tumor-focused improvements in the physicochemical and pharmacokinetics properties
near-infrared (NIR) light irradiation, photosensitizers (PSs) rapidly of PSs, tumor targeting delivery, and enhancement of combined therapy
generate cytotoxic reactive oxygen species (ROS) (Fig. 2) and kill tumor [58]. In recent years, the emerging photodynamic nanotherapeutics for
cells [44]. Notably, ROS generated from PSs can not only promote tumor inducing ICD and potentiating cancer immunotherapy have aroused
cell death but also trigger endoplasmic reticulum (ER) pressure and growing interest in cancer therapy [59–61]. In view of the rapid
elicit CRT exposure, thus inducing ICD of tumor cells and releasing development of photodynamic nanotherapeutics in inducing ICD and
pro-inflammatory cytokines and DAMPs [47,48]. However, the short potentiating cancer immunotherapy, we summarize and outline the

Fig. 1. Schematic representation of the cycle process

of immune response in tumor cells. First, antigens and
DAMPs were released from dying tumor cells. Then,
antigens were presented by antigen-presenting cells
(APCs) to promote the maturation of DCs. Antigens
were further presented to T cells in lymph nodes,
resulting in the priming and activation of T cells.
Finally, activated effector T cells were trafficked and
infiltrated to tumor tissues, where they could recog­
nize and kill tumor cells.

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S. Zhang et al.
latest updates in this field from various induction strategies (Fig. 3,
Table 1). Moreover, we also make some classifications of biomaterials
and PSs used in the development of ICD-based photodynamic nano­
therapeutics (Fig. 4). Finally, we briefly discuss the design principles,
advantages, challenges and future prospects of ICD-based photodynamic
nanotherapeutics in clinical cancer therapy. This paper could provide
reference for the design and construction of photodynamic nano­
therapeutics to induce ICD and enhance cancer immunotherapy.
2. Photodynamic nanotherapeutics for ICD induction
Recently, PDT has been found to effectively induce ICD and poten­
tiate the immune response [62–72]. However, there are plenty of chal­
lenges for PDT-mediated induction of ICD, such as short half-life and
aggregation caused quenching (ACQ) effect of most PSs, tumor hypoxia
microenvironment and inefficient accumulation of PSs in ER. Recently,
several emerging photodynamic nanotherapeutics have been developed
to deal with multiple stages of obstacles in the whole drug delivery
process [49,65,73–75]. In this section, we will discuss the emerging
photodynamic nanotherapeutics for ICD induction, including targeting
induction of ICD with biomimetic photodynamic nanotherapeutics,
remodeling unfavorable tumor microenvironment (TME) for PDT, pre­
cisely targeting to ER and addressing the ACQ effect of PSs.
2.1. Biomimetically targeting induction of ICD
Compared with conventional nanocarriers, cell membrane-derived
nanoplatform has emerged as an effective and promising biomimetic
strategy for enhancing PDT efficiency [62–67]. Particularly, it has been
demonstrated that nanoparticles (NPs) wrapped with or embedded in
cancer cell membranes (CCM) can significantly improve tumor targeting
capacity, thus greatly improving the efficacy of PDT-induced ICD
[62–66]. For instance, Han et al. designed 4T1-Fluc CCM-modified li­
posomes loading with KillerRed (a photosensitizer, KR) for improving
the tumor-homing ability. Firstly, the 4T1-Fluc cancer cells transfected
with mem-KR plasmids were extracted. Then, KR-CCM, MPLA adjuvant
(A), and helper lipids (Lp) were hybridized to prepare lipocomplex
(Lp-KR-CCM-A) via thin-film hydration and serial extrusion. Notably,
Fig. 3. Schematic representation of emerging photodynamic nanotherapeutics
for inducing immunogenic cell death and potentiating cancer immunotherapy.
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Biomaterials 282 (2022) 121433
the accumulation of Lp-KR-CCM-A in tumor was improved by 3.3 times
compared with that of Lp-A owing to the high affinity to homologous
tumor cells [64]. The effective distribution of KR in tumor tissues
enabled the generation of large amounts of ROS under laser irradiation
and elicited robust ICD with the release of DAMPs. Meanwhile, the host
immune response was activated, including the maturation of DCs and
the proliferation of cytotoxic T lymphocytes (CTLs). As a result, the
activated immune system significantly inhibited the growth of primary
tumor and the lung metastasis in an ectopic 4T1 tumor-bearing mouse
model [64].
In addition to CCM, immune cell membranes (ICM) have also been
used to develop biomimetic nanotherapeutics, such as neutrophils, DCs
and natural killer (NK) cells [65,67]. ICM-camouflaged NPs could not
only increase tumor targeting efficiency but also induce the secretion of
pro-inflammatory cytokines. For instance, Deng et al. recently devel­
oped NK cell membrane-coated poly (lactic-coglycolic acid) (PLGA) NPs
(NK-NPs) loading with 4, 4′ , 4′′ , 4′′′ -(porphine-5, 10, 15, 20-tetrayl)
tetrakis (benzoic acid) (TCPP, a photosensitizer) for cancer immuno­
therapy (Fig. 5) [65]. NK-NPs could be effectively accumulated in tumor
tissues to evoke ICD and facilitate release of DAMPs, including amount
CRT exposure induced, secreted ATP and HMGB1 release under NIR
light illumination, thus propelling the maturation of DCs and increasing
the percentage of infiltrating T cells (CD4+ or CD8+) [65]. Moreover, NK
cell membrane was found to participate in inducing the polarization of
M1 macrophages and the secretion of cytokines, and further enhancing
the infiltration of effector T cells [65]. In the 4T1 tumor model, both
primary tumors and distant tumors were significantly inhibited after
PDT treatment of NK-NPs.
Moreover, nanosystems modified with hybrid cell membranes were
also explored as multi-functional nanoplatforms. For example, a nano­
system engineered from hybrid membranes of cancerous 4T1 cells and
DCs was developed for reinforcing cancer immunotherapy [66]. Briefly,
TCPP was dispersed in the metal-organic frameworks (MOFs), and the
MOFs were further surrounded by hybrid cytomembranes to construct
unique NPs (PCN@FM) [5]. PCN@FM exhibited excellent tumor
self-targeting ability due to the coating of functional hybrid cytomem­
branes (4T1 cells and DCs) [66]. Besides, under NIR light illumination,
multiple-stimulation of the released DAMPs, immune co-stimulatory
molecules and highly expressed antigen on hybrid cytomembranes
could synergistically enhance the activation and the tumor infiltration of
CTLs [66]. Consequently, both the primary and abscopal tumors in
4T1-tumor-bearing mice were almost entirely eliminated [66].
Except cell membranes, some serum proteins were also used to
develop biomimetic photodynamic nanosystems. For instance, Chen
et al. designed a bioinspired nanocarrier loaded with chlorine e6 (Ce6),
which was coated by hybrid protein composed of human serum albumin
(HSA) and hemoglobin (Hb) [76]. As an endogenous protein, HSA shows
good biocompatibility and specific tumor-targeting ability. As a result,
the HAS-modified nanosystem (C@HPOC) significantly promoted the
accumulation of Ce6 in tumor tissues [76]. Under laser irradiation, Ce6
produced large amounts of ROS in killing tumor cells accompanied by
CRT exposure, ATP secretion and HMGB1 release from 4T1 cells, and
then promoted DC maturation [76]. In a bilateral metastatic
triple-negative breast cancer model, the growth of primary tumors was
significantly suppressed and the distant tumors were also obtained
effective treatment attributed to the activated host immune system.
More importantly, C@HPOC plus laser treatment against primary 4T1
tumors could extremely prevent the occurrence of lung metastasis [76].
Collectively, these results demonstrated PDT-induced ICD could elicit an
intense antitumor immune response, which accordingly contributed to
promising abscopal and anti-metastatic effect [76].
2.2. Remodeling the undesirable TME
As discussed above, biomimetic strategy has been found to signifi­
cantly increase the specific accumulation of PSs in tumors, which
S. Zhang et al. Biomaterials 282 (2022) 121433

Table 1
Main strategies and characterizations of the emerging photodynamic nanotherapeutics for inducing ICD and potentiating cancer immunotherapy.
Classifications Strategies Nanoplatforms Functions Refs.

Photodynamic NPs for ICD
Induction
PDT-based Synergistic Induction
of ICD
Multimodal Cancer
Immunotherapy in basis of
PDT-induced ICD
Biomimetically Targeting
Induction of ICD
Remodeling the
Undesirable TME
Precisely Targeting ER
Addressing the ACQ Effect
Photothermal/
Photodynamic Synergistic
Induction
Chemo-photodynamic
Synergistic Induction
Other Synergistic Induction
Combos
Combination with
Adjuvants or Vaccines
Combination with
Checkpoint Blockade
Combination with Other
Therapeutics
Cancer cell membranes-decorated Enhanced homologous targeting 62–64
photodynamic NPs
Immune cell membranes-decorated Enhanced homologous targeting and the 65, 67
photodynamic NPs secretion of pro-inflammatory cytokines
Hybrid cell membranes-decorated Enhanced immunogenicity and tumor-targeting 66
photodynamic NPs ability
Serum proteins-decorated Enhanced tumor-targeting ability 76
photodynamic NPs
Photodynamic NPs based on Enhanced penetration of photodynamic NPs 68, 69
destroying tumor extracellular matrix
Upconversion-based photodynamic Stronger penetration ability of light 70-72, 77
NPs
Photodynamic NPs loaded with Catalyzing H2O2 to produce oxygen 73, 78-83
metallic oxides or catalase
Photodynamic NPs loaded with Reducing oxygen consumption 59, 84, 85
mitochondrial respiration inhibitor
ER-targeting photodynamic NPs Enhancing ER stress and CRT exposure 48, 49
Acid-responsive photodynamic NPs Accelerating drug release and addressing ACQ 86
effect
Redox-responsive photodynamic NPs Accelerating drug release and addressing ACQ 63, 75
effect
Dual-responsive photodynamic NPs Accelerating drug release and addressing ACQ 74, 87
effect
Photodynamic NPs loaded with PTT + PDT 92, 99
organic PSs
Inorganic photodynamic NPs such as PTT + PDT 48, 95-98
Au NPs, black phosphorus NPs and etc.
Photodynamic NPs integrated with Chemotherapy + PDT 74, 88, 90, 101
chemical drugs such doxorubicin or
oxaliplatin
Photodynamic NPs integrated with Radiotherapy + PDT 114, 115
radiation-activatable PSs
Photodynamic NPs loaded with Sonodynamic therapy + PDT 122, 23
photo/sonosensitizers
Integrating PSs with nanovesicles Carrier-based ICD + PDT 91
enabling ICD induction
Photodynamic NPs loaded with Enhancing the PDT-based antigen presentation 131–133
adjuvants
Photodynamic NPs loaded with Combination of vaccines and the PDT-based 134, 135
vaccines DAMPs release
Photodynamic NPs integrated with Combination of PD-1/PD-L1 blockade-based 86, 125, 130,
anti-PD-1/PD-L1 immunotherapy and PDT 138 139, 142
Photodynamic NPs integrated with Combination of CTLA-4 blockade-based 92, 129
anti-CTLA-4 immunotherapy and PDT
Photodynamic NPs integrated with Combination of IDO blockade-based 50, 191, 105,
IDO inhibitor immunotherapy and PDT 126, 128, 147,
148
Photodynamic NPs integrated with Combination of OX40 or TIM-3 checkpoint- 152, 157
checkpoint inhibitors or agonists based immunotherapy and PDT
Photodynamic NPs integrated with Combination of immunotherapy strategy based 127, 158
imatinib or sorafenib on suppressing the immunosuppressive cells and
PDT

contributes to the induction of ICD under laser irradiation [62–67].
However, the extremely intricate TME still imposes multiple barriers to
PDT and PDT-induced ICD, such as the compact tumor extracellular
matrix (ECM), limited penetration ability of light into tumor tissues and
tumor hypoxia [68–73]. It has been widely accepted that overcoming
these barriers within TME is of crucial importance for efficient PDT and
PDT-induced ICD.
Compact ECM has been found to be a major barrier to tumor deep
penetration of nanomedicines [68–72]. Recently, a variety of nano­
systems have been designed to improve the tumor penetration of PSs for
more efficient PDT and PDT-induced ICD [68–72]. For instance, Wang
et al. developed a hyaluronidase (HAase)-modified dextran (DEX)
polymer containing a pH-responsive linker for the degradation of the
cross-linked hyaluronic acid (HA) in the ECM, thus enhancing the
penetration capacity of PSs and then improving PDT and ICD induction
efficiency [68]. After accumulation at tumor sites, preinjected HAase
was released from the DEX-HAase NPs triggered by acidic stimuli to
loosen the ECM structure through degradation of HA [68].
Subsequently, following treatment with Ce6@liposome exhibited the
enhanced intratumor penetration and more significant suppression in
4T1 tumor-bearing BALB/c mice [68]. Moreover, the increased tumor
infiltration of CTLs was observed in the group of DEX-HAase plus PDT
(enhanced PDT), which could be ascribed to the release of TAAs after the
enhanced PDT-induced ICD [68]. Therefore, the combination therapy of
the enhanced PDT and anti-PD-L1 combination therapy displayed a
more significant suppression on both primary tumors and distant tumors
in 4T1 tumor-bearing BALB/c mice under laser irradiation [68]. In
addition to HAase, Melittin (MLT) has also been found to enhance the
deep penetration of tumors by disrupting prokaryotic and eukaryotic
cell membranes, which has also been utilized to facilitate the accumu­
lation of PSs in tumors [69]. For instance, Liu et al. developed serum
albumin (SA)-coated boehmite NPs loading with both Ce6 and MLT
peptide via electrostatic interactions, denoted as Ce6/MLT@SAB [69].
Formulating MLT into the nanosystem coated with the SA not only
reduced the hemolysis of MLT, but also significantly enhanced the
penetration of Ce6 in tumors [69]. Under laser irradiation, because of

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S. Zhang et al.
Fig. 4. Brief classifications and typical examples of photodynamic nanotherapeutics to induce ICD of tumor cells according to biomaterials and PSs.
Fig. 5. Schematic iIllustration of NK cell-membranes-cloaked NPs for PDT-enhanced cell-membrane immunotherapy [65]. Reprinted with the permission from (Deng
et al., 2018). Copyright (2018), American Chemical Society.
the increased penetration effect of MLT, Ce6/MLT@SAB evoked a more
intense ICD following the CRT exposure and ATP release, and promoted
the maturation of DCs and the tumor infiltration of CD4+ and CD8+ T
cells, resulting in augmented PDT-based immunotherapy in 4T1
tumor-bearing BALB/c mice [69].
In addition to the inefficient tumor penetration of nanocarriers, the
limited tissue penetration of laser also significantly affects PDT-based
ICD. Generally, the long-wavelength light has better security and
stronger penetration ability than the short-wavelength NIR light [70–72,
77]. Upconversion NPs (UCNPs) have been extensively investigated to
improve the problems of the low energy of long-wavelength light and
the poor penetration of short-wavelength light into tumor tissues to
activate PSs and enhance PDT-based induction of ICD [70–72,77]. For
instance, Xu et al. reported multitasking UCNPs consisted of 20% of Yb
and 2% of Er-doped NaYF4. Then, the UCNPs were further coated by
amphiphilic polyethylene glycol (PEG)-grafted poly (maleic anhy­
dride-alt-1-octadecene) (C18PMH-PEG). Finally, both Ce6 and
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Biomaterials 282 (2022) 121433
imiquimod (R837) were loaded between the UCNP core and the PEG
shell by virtue of hydrophobic interactions [70]. Under the excitation of
980 nm NIR light, two upconversion luminescence peaks (550 and 660
nm) were emitted from those UCNPs. The emissive 660 nm laser could
excite Ce6 via the resonance energy transfer. As a result, the
UCNP–Ce6-R837 NPs-mediated PDT exhibited a more potent antitumor
efficacy than other control groups on mice bearing CT26 tumors [70].
Moreover, both TAAs from cell residues post-PDT and immunoadjuvant
R837 could collaboratively elicit ICD and evoke robust antitumor
response to eliminate the distant tumor [70]. In the further evaluation of
immune response, the proportions of effector memory T cells of the
UCNP–Ce6-R837 NPs-mediated PDT were significantly elevated, per­
forming an effective inhibition on the rechallenged CT26 tumors [70].
Furthermore, polydopamine (PDA)-encapsulated core–shell UCNPs with
Ce6 (PDA@UCNP-PEG/Ce6 NPs) were also constructed to realize deep
tissue penetration of visible light via conquering the aberrant TME in
solid tumors [72]. Firstly, PDA with good photothermal conversion
S. Zhang et al.
efficiency was used as the inner core, and then lanthanide (Ln)-doped
carbonate hydroxide layer (Gd:Yb,Er(OH)CO3) was coated onto the PDA
core to construct the PDA@Ln (OH)CO3 NPs. Finally,
PDA@UCNP-PEG/Ce6 NPs were obtained by loading Ce6 onto PDA@Ln
(OH)CO3 NPs via the mixed stir with multiarm PEG polymers [72].
Under the irradiation of 980 nm laser, PDA@UCNP-PEG/Ce6 NPs
exhibited the high abilities of photothermal conversion and upconver­
sion emission at 663 nm for the excitation of Ce6 molecules [72]. As a
result, the designed PDA@UCNP-PEG/Ce6 effectively eliminated the
primary tumor and furtherly prevented the metastasis and relapse of
tumor through the ICD induced by the DAMPs release and the activation
of antitumor response in a 4T1 tumor-bearing mouse model [72].
Moreover, hypoxia is another feature of the TME in solid tumors,
which has also been found to severely imped PDT-based ICD. Tumor-
specific oxygen supply has been widely accepted as an efficient strat­
egy to alleviate hypoxia [73,78–82]. Some metallic oxides, such as
copper oxide, manganese oxide, and ferric oxide, are often used to
catalyze H2O2 to produce oxygen [73,78–81]. For instance, Liang et al.
designed a core-shell gold nanocage modified with manganese dioxide
(AuNC@MnO2) as an oxygen supplier for PDT to enhance immuno­
therapy (Fig. 6) [73]. When exposed to acidic stimuli at tumor sites,
MnO2 in the shell of the AuNC@MnO2 NPs reacted with H2O2 to release
oxygen in situ to overcome hypoxia, thus facilitating the generation of
ROS and the ICD induction of 4T1 tumor cells. Subsequently, these ICD
signal molecules (CRT, ATP, HMGB1) from 4T1 tumor residues could
promote the maturation of DCs and the activation of T cells [73]. In a
4T1 tumor xenograft BALB/c mouse model, AuNC@MnO2 NPs exhibited
potent antitumor activity, ablating the primary tumors under NIR light
irradiation and preventing tumors metastasis due to the activated im­
mune system [73]. Moreover, Lan et al. constructed a MOF-based
nanoplatform composed of Fe3O clusters and TBP (a photosensitizer)
[79]. Upon exposed to hypoxic environment, intracellular H2O2 would
Fig. 6. Schematic illustration of the design and function of AuNC@MnO2 (AM) as TME responsive oxygen producer for oxygen-boosted immunogenic PDT [73].
Reprinted with the permission from (Liang et al., 2018). Copyright (2018), Elsevier Ltd.
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Biomaterials 282 (2022) 121433
be catalyzed by Fe3O to supply oxygen via Fenton-like reaction [79].
The ameliorative hypoxic condition facilitated the generation of ROS
from TBP under NIR light irradiation. As a result, in vivo high CRT
expression and CTLs was measured in Fe-TBP treated tumor tissue,
which indicated the CT26 tumor cells underwent ICD and the host im­
mune response was successfully evoked. In a bilateral model of CT26
tumors, Fe-TBP NPs significantly inhibited the growth of primary and
distant tumor by efficiently eliciting the PDT-based ICD and promoting T
cell activation and infiltration in tumor [79]. Moreover, catalase (CAT)
was also utilized to catalyze H2O2 to produce oxygen in solid tumors,
Zhang et al. and Meng et al. have reported related studies [82,83].
Other from catalyzing H2O2 to boost oxygen concentration, another
alternative strategy is to reduce oxygen consumption within tumor cells.
Metformin (Met), a commonly used hypoglycemic agent, has recently
been found to effectively inhibit mitochondrial respiration [59,84,85].
Mai et al. designed platelet membranes (PM) as a multifunctional
nanoplatform to co-encapsulate IR780 and Met (PM-IR780-Met NPs)
[59]. Met could strikingly reduce tumor oxygen consumption through
inhibiting mitochondrial respiration, thereby promoting IR780-induced
PDT and ICD-based immunotherapy [59]. Under NIR light irradiation,
PM-IR780-Met NPs displayed effective PDT and DAMPs were released
from dying tumor cells following with the occurrence of ICD [59].
Meanwhile, the relieved tumor hypoxia could also reduce the immune
suppressive cells to further enhance the antitumor therapy. Finally,
tremendous CTLs cells were recruited and invoked, providing a prom­
ising platform for elimination of the primary tumors and prevention of
the lung metastasis in a 4T1 tumor bearing mouse model [59].
2.3. Precisely targeting ER
ER pressure has been found to be a key factor for the release of
DAMPs. Therefore, accurately targeting of PSs to ER is of great
S. Zhang et al.
importance for the induction of ICD [48,49]. For example, Li et al. re­
ported indocyanine green (ICG)-coupled hollow gold NPs (FAL-IC­
GHAuNS), which were decorated with ER-targeting pardaxin (FAL)
peptides (Fig. 7) [48]. Moreover, a FLA-modified liposome containing
the oxygen-supplying Hb was integrated into the system to alleviate
hypoxia [48]. The composite nanosystem induced robust ER pressure
under laser irradiation. As a result, a large amount of CRT was exposed
on cell membrane to stimulate the maturation of DCs and the prolifer­
ation of CD8+ cells [48]. The ER-targeting nanosystem effectively acti­
vated the dormant host immune system, facilitating a potent
ICD-associated immunotherapy in a B16 tumor-bearing mouse model
[48].
In addition to modifying nanocarriers with ER-targeting ligands,
formulating PSs with ER-targeting capacity into nanocarriers represents
another strategy for PDT-based ICD induction. For instance, Deng et al.
designed and synthesized an ER-targeted photosensitizer, named TCPP-
TER, which was loaded into reduction-sensitive Ds-sP NPs through thiol-
disulfide exchange reaction [49]. When exposed to the high level of
glutathione (GSH) in tumor cells, TCPP-TER could be quickly released
from the Ds-sP/TCPP-TER NPs. Then, TCPP-TER was selectively accu­
mulated in ER to induce intense ER pressure by the generated abundant
ROS [49]. Both in vitro and in vivo results demonstrated that ER-targeting
PDT could elevate ICD level and promote release of DAMPs [49]. In a
4T1 tumor-bearing mouse model, Ds-sP/TCPP-TER NPs-mediated PDT
exhibited potent antitumor effect for the primary tumors [49].
Furthermore, an outstanding anti-distant tumor effect was obtained in
the Ds-sP/TCPP-TER NPs-treated group [49]. Meanwhile, the augmented
secretion of cytokines and infiltration of CD8+ T cells were observed at
the tumor tissue, suggesting that the ER-targeting PDT strategy could
amplify immunotherapeutic efficiency to inhibit the growth and
metastasis of tumors [49].
2.4. Addressing the ACQ effect
Although a variety of nanomaterials have been used for improving
the delivery efficiency of PSs, the ACQ effect of PSs trapped in large
Fig. 7. The antitumor mechanism of FAL-ICG-HAuNS plus FAL-Hb-lipo. Schematic illustration of enhanced immunogenic cancer cell death and anticancer effect
induced by ER-targeting photothermal therapy (PTT)/PDT [48]. Reprinted with the permission from (Wei et al., 2019). Copyright (2019), Nature Communication
Publishing Group.
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Biomaterials 282 (2022) 121433
amounts of carrier materials has long been a challenge for PDT [75,86].
The ACQ effect significantly impairs the generation and diffusion of
ROS. Therefore, how to realize tumor-specific release of PSs from
nanocarriers is of crucial importance for PDT-based immunotherapy.
Compared to normal tissues, most tumors are characterized with highly
acidic and redox microenvironment [75]. Recently, several tumor
stimuli-responsive nanosystems loaded with PSs have been developed to
address the ACQ problems and to promote PDT-based cancer immuno­
therapy [63,75,86]. For instance, Wang’s group developed
acid-activatable cationic nanomicelles co-loaded with PSs (Pyropheo­
phorbide a, PPa) and small interfering RNA (siRNA) [86]. After the
tertiary amino groups of pH-responsive diblock copolymer fully pro­
tonated in the acidic TME, the designed micelleplexes were dissociated,
and PPa was rapidly released from the nanosystem [86]. Upon NIR light
treatment at pH 6.0, the nanomicelles generated much more ROS
(5.6-fold) than that at pH 7.4, resulting in more efficient ICD of B16–F10
tumor cells [86]. The high expressions of heat shock protein 70 (HSP70)
and NF-κB in B16–F10 tumor cells were observed in the treatment group
of pH-responsive nanomicelles, suggesting the activation of the innate
and adaptive immune response [86]. As a result, the pH-responsive
nanomicelles showed significant inhibition on tumor growth and
metastasis by evoking antitumor immune response and recruiting tumor
infiltrating CD4+ and CD8+ T cells in a B16–F10 melanoma xenograft
tumor model.
In addition to acidic stimulation, high concentrations of intracellular
GSH and ROS were also utilized to develop redox-responsive photody­
namic nanotherapeutics for alleviation of the ACQ of PSs [63,75]. For
instance, Liu et al. designed redox-activated liposomes (RAL) consisted
of disulfide bond-linked phospholipid-porphyrin conjugates [75]. Upon
internalization into tumor cells, porphyrin could be rapidly released in
the presence of high concentration of intracellular GSH, thereby acti­
vating the fluorescence signal and ROS generation capacity of porphyrin
[75]. Moreover, GSH depletion contributed to the sensitivity of PDT
[75]. Under NIR light irradiation, efficient PDT-induced ICD of tumor
cells following with CRT exposure, HMGB-1 release, and ATP secretion
was observed, and more activated CTLs were transferred to tumor
S. Zhang et al.
tissues, effectively eradicating the primary tumors and contralateral
tumors and preventing the occurrence of metastatic nodules in 4T1
breast tumor-bearing mice [75].
Moreover, several dual-responsive nanosystems have been devel­
oped for PDT-based ICD and immunotherapy [74,87]. Compared with
the single-responsive nanosystem, the dual-responsive NPs could release
PSs more quickly, and sufficiently alleviate the ACQ effect and enhance
PDT efficiency [74,87]. For instance, Wang et al. fabricated
GSH/pH-triggered mesoporous organosilicas (MONs) loaded with Ce6,
and was further modified with magnetic heads (M-MONs@Ce6). In
comparison with the single stimulation of GSH or acid, M-MONs@Ce6
exhibited more thorough degradation and faster drug release, which
enhanced the photodynamic efficiency of Ce6 and reduced the toxicity
to normal tissues [87]. When exposed to NIR light and alternating cur­
rent magnetic field (ACMF), the nanosystems induced the greatest
amount of CRT exposure and HMGB1 release to evoke robust ICD of
tumor cells, due to efficient generation of ROS and magnetic hyper­
thermia. The induced ICD could further promote DCs maturation and T
cells activation, priming tumor-specific immune response in 4T1
tumor-bearing mice [87]. Consequently, the activated immune response
exhibited highly effective suppression on both primary tumors and
metastatic tumors in 4T1 tumor-bearing mouse models [87].
3. PDT-based synergistic induction of ICD
Though PDT has been extensively explored to induce ICD, there are
still some inherent limitations of PDT that are not sufficient to evoke a
strong immune response [88,89]. Recently, multiple combined thera­
peutic strategies have been used to elevate the efficiency of ICD by
compensating the deficiencies of a single PDT [90–92]. The synergistic
efficacy to induce ICD can be achieved by combining PDT with
chemotherapy, PTT, radiotherapy and so on.
3.1. Photothermal/photodynamic synergistic induction
Similar to PDT, non-invasive PTT can convert light into heat energy,
which enables the temperature of the cells to be heated up rapidly,
killing the cell in the form of thermal ablation [93,94]. Recent studies
also described that PTT could cause antigen release and activate im­
mune response, resulting in significant enhancement in the level of ICD
via combining with PDT [95,96]. Apart from acting as a photosensitizer
for PDT, ICG also can serve as a light absorber for PTT [92]. Wang’s
group fabricated a light-triggered and antigen-capturing UCNPs-based
nanoplatform (UCNP/ICG/RB-mal), which was obtained by assembling
ICG and DSPE-PEG-maleimide onto UCNPs and then loading the
photosensitizer rose bengal (RB) [92]. In the nanoplatform, PDT and
PTT can be simultaneously achieved to enhance the release of antigens
under the NIR laser irradiation [92]. In addition, the TAAs and DAMPs
released from 4T1 cells could be captured in situ due to the maleimide,
further enhancing the uptake and presentation of tumor antigens [92].
In vivo results demonstrated that the synergistic treatment of PDT and
PTT significantly inhibited the growth of primary and distant 4T1 tu­
mors, contributing to a potent therapeutic effect in a highly metastatic
4T1 mammary tumor model [92]. Moreover, due to the effective in­
duction of ICD, the combination group of UCNP/ICG/RB-mal and im­
mune checkpoint blockade (ICB) successfully rejected 4T1 tumor
rechallenge and realized long-term immune response [92].
Due to the intrinsic absorption to light, amounts of inorganic nano­
therapeutics such as Au NPs [48,96], CuS NPs [97], ZrC [98] or black
phosphorus NPs [95] have been developed for PTT. Liu et al. constructed
an ultrasmall gold nanocluster (Au25Capt18) for the combined PTT and
PDT against skin cancer [96]. Upon laser irradiation, the prepared Au
NPs could generate high level of photothermal energy and ROS, eliciting
robust ICD of cutaneous squamous cell carcinoma [96]. In addition to
metallic material, some polymers have also been applied for PTT in
combination strategies for potentiating ICD induction. For instance, Yan
8
Biomaterials 282 (2022) 121433
et al. developed PDA-encapsulated Ce6-loaded core–shell UCNPs for
PTT&PDT induced ICD [99]. Upon laser irradiation, the PDA core could
perform an optimal photothermal effect for PTT while synchronously
optimized the generation of ROS for PDT [99]. The combinational
application of PDT and PTT in vivo effectively promoted the release of
TAAs and DAMPs, triggered the maturation of DCs and robustly acti­
vated CTLs against the metastasis and relapse of 4T1 tumors [99]. Taken
together, the photothermal/photodynamic combination offers a
high-efficiency synergistic therapeutic modality for cancer
immunotherapy.
3.2. chemo-photodynamic synergistic induction
In addition to PDT, recent evidence has revealed that some chemo­
therapeutic drugs such as oxaliplatin (Oxa), cyclophosphamide, pacli­
taxel (PTX) or Dox could also induce ICD of tumor cells and provoke the
host immune response [26,88,100–104]. Therefore, the combination of
PDT and chemotherapy will initiate a stronger immune response than
PDT and chemotherapy alone [74,88,101,105]. For instance, He et al.
developed a core-shell nanoscale coordination polymer (NCP) contain­
ing Oxa and photosensitizer pyropheophorbide-lipid conjugate (pyroli­
pid) [88]. In bilateral tumor models of MC38, the effective
chemo-photodynamic synergistic therapy between Oxa and PPa pro­
voked a high level of ICD, leading to CRT exposure, antitumor vacci­
nation and an abscopal effect [88]. Recently, Huang et al. developed
engineered macrophages (Oxa (IV)@ZnPc@M) carrying nanostructured
lipid, Oxa precursors and Zinc phthalocyanine (ZnPc, as PSs) [90].
Firstly, Zn2+ was crosslinked with the carboxyl group of Oxa prodrug to
form the core, and ZnPc was simultaneously loaded in the lipid bilayer
through hydrophobic interaction for the construction of Oxa (IV)@ZnPc
(Fig. 8) [90]. Then, Oxa (IV)@ZnPc was further loaded into macro­
phages to improve tumor-targeted ability [90]. Under NIR light irradi­
ation, drugs inside Oxa (IV)@ZnPc were released and then performed a
combined chemo-photodynamic therapy with the second laser, which
led to successfully kill 4T1 primary tumors [90]. Meanwhile, DAMPs
released from killed 4T1 tumor cells could cause ICD of tumor cells and
potentiate the antitumor immune response against primary and bone
metastatic tumors in a 4T1-bearing mouse model [90].
In addition to Oxa, existing researches also clarified the capability of
Dox for ICD induction [74,101,106]. Hu’s research group designed a
cascade chemo-photodynamic therapy (Ce6/Dox) with ROS-responsive
lipid-polymer hybrid NPs (TKHNP-C/D) to promote ICD and tumor
immunotherapy [101]. Under 660 nm light irradiation, Dox was rapidly
released through the degradation of the designed nanocarrier, formu­
lating an efficient synergy with PDT to stimulate the maturation of DCs
and the infiltration of T cells [101]. Furthermore, a dual-sensitive
(GSH/pH) prodrug-based nanoplatform was designed by conjugating
5-aminolevulinic acid (5-ALA, as PSs) and Dox via hydrazine backbones
and disulfide bonds [74]. When exposed to the intracellular TME, the
dual-response prodrug self-assembly NPs could rapidly release 5-ALA
and Dox, and the 5-ALA was subsequently converted to protoporphy­
rin IX (PpIX) by intracellular enzyme catalysis [74]. Under NIR light
irradiation, the generated ROS and the released Dox synchronously
induced ICD with the release of calreticulin, HMGB1, and ATP from
dying 4T1 cells. These released DAMPs subsequently activated DCs and
stimulated host immune response to lead to the increased number of
CTLs at tumor site [74]. Ultimately, the prodrug-based chemo-­
photodynamic strategy not only significantly reduced the undesirable
side effects but also markedly inhibited the growth and metastasis of
tumor in a 4T1 mouse model [74].
3.3. Other synergistic induction combos
In addition to some conventional treatments, the combination of PDT
with radiotherapy or sonodynamic therapy has also been explored to
synergistically induce ICD [91,107,108]. Radiotherapy involves one or
S. Zhang et al. Biomaterials 282 (2022) 121433

Fig. 8. The preparation and mechanism of the artificially engineered macrophages. a Schematic illustration of the preparation of Oxa (IV)@ZnPc@M. b The
mechanism of Oxa (IV)@ZnPc@M mediated chemo-photodynamic therapy to trigger robust antitumor immune responses and potentiate PD-L1 blockade immu­
notherapies for anti-primary and bone metastatic tumors [90]. Reprinted with the permission from (Wei et al., 2021). Copyright (2021), Nature Communication
Publishing Group.

more kinds of ionizing radiation such as X-rays and high-energy electron
beams to induce the DNA damage in tumor cells [109,110]. Recently,
there’s evidence that radiotherapy-induced DNA damage is capable of
triggering ICD and stimulating T cell proliferation [109,110]. Moreover,
the combination of low dose photosensitizer and early radiotherapy can
significantly enhance PDT-based antitumor immune response [111].
Benefiting from the excellent tissue penetration of X-rays, researchers
have utilized scintillators and metals to transfer the energy of X-rays to
PSs for boosting PDT efficacy [107,112–115]. For instance, Lu et al.
constructed 5, 15-di (p-benzoato) porphyrin-Hf (DBP-Hf) MOFs and 5,
10, 15, 20-tetra (p-benzoato) porphyrin-Hf (TBP-Hf) MOFs based on Hf
clusters and porphyrin-based PSs [114]. On the one hand, X-ray photos
could be absorbed by Hf clusters and produced •OH radicals for
radiotherapy. On the other hand, X-ray triggered the generation of 1O2
from PSs to facilitate PDT, which was known as radiodynamic therapy
(RDT) [114]. Under the induction of X-rays, MOFs loaded with
indoleamine-pyrrole 2, 3-dioxygenase (IDO) inhibitor (IDOi@nMOFs)
significantly promoted the CRT exposure and evoked ICD, and the
released antigens enabled the effective tumor infiltration of CD8+ T cells
via radiotherapy-radiodynamic therapy in syngeneic mouse models of
breast and colorectal cancers [114]. Additionally, the distant tumor
growth was also remarkably suppressed, suggesting the excellent sys­
temic immune responses caused by IDOi@nMOFs [114].
Additionally, sonodynamic therapy (SDT) is also a local therapy
modality that uses ultrasound to activate sonosensitizers for ROS gen­
eration [116]. The combination of PDT and SDT has been investigated to

9
S. Zhang et al.
enhance the anti-tumor effect and reduce the toxic side effects [117,
118]. Notably, the fragments produced by SDT-mediated apoptotic or
necrotic cancer cells were able to act as antigens to activate host anti­
tumor immunity [119–121]. More importantly, SDT-PDT synergistic
induction can efficiently evoke ICD, thereby activating a robust immune
response [122,123]. Particularly, two-dimensional (2D) carbon nitride
(g-C3N4) nanosheets with good biocompatibility and abundant surface
amino groups have been utilized for efficient delivery of photo/­
sonosensitizers [123,124]. For instance, Chen et al. designed a
metal-free g-C3N4/Ce6 nanohybrid for combined immunotherapy
[123]. Ce6 was loaded in the nanosheets and acted as a dual-functional
photo/sonosensitizer [123]. The nanohybrids not only displayed potent
cytotoxicity against 4T1 cells, but also effectively promoted the matu­
ration of DCs after NIR light and ultrasound treatment in vitro [123]. The
nanohybrids effectively stimulated immune responses in vivo, resulting
in potent tumor immunotherapy in 4T1 tumor-bearing mice [123].
In addition to combinations mentioned above, more interestingly,
the researchers found that some versatile nanomaterials could also be
used to enhance the ICD [91]. Yang et al. designed a unique
nanovesicle-mediated and PDT-based nanoassemblies [91]. The
pH-responsive nanovesicles (pRNVs) composed of block copolymer
polyethylene glycol-b-cationic polypeptide, acted as not only a carrier
but also an ICD inducer [91]. Compared to HPPH-mediated PDT alone,
such pRNVs loaded with HPPH could impressively elevate the ICD level
of tumor cells with high CRT exposure, TAAs secretion, DC recruitment,
maturation, migration, and CD8+ T cell activation, resulting in a potent
suppression on primary and distant tumors in a B16F10 melanoma
tumor model [91]. Overall, these findings suggest that the combination
of PDT and other therapeutics could efficiently enhance the ICD levels of
tumor cells induced by PDT alone and stimulate an intense antitumor
immune response.
4. Multimodal cancer immunotherapy in basis of PDT-induced
ICD
Nowadays, diverse strategies have been explored for enhancing PDT
and inducing ICD of tumor cells to activate the host immune response
against cancer [125–127]. However, cancer immunotherapy is an
extremely complicated process, which can be broadly summarized in
three stages: (i) antigen presenting stage; (ii) effector T cell proliferation
and differentiation stage; and (iii) tumor elimination stage [128]. The
ICD of tumor cells is regarded as the largest contributor to the first stage
of immunotherapy [128]. Whereas, the failure at any of these stages can
easily diminish the effectiveness of cancer immunotherapy [128]. For
example, IDO can attenuate the activation of effector T cells [128];
cytotoxic T lymphocyte antigen 4 (CTLA-4) can suspend the activated T
cells and mediate the inhibitory function of regulatory T (Treg) cells
[129]; and PD-1/PD-L1 can interfere with the recognition of tumor by
effector T cells, all of which can reduce the treatment efficiency of tumor
immunotherapy [130]. Therefore, single-modal cancer immunotherapy
based on PDT-driven ICD is not enough to attain a satisfactory therapy
outcome. It is necessary to combine ICD-based PDT with other immu­
notherapies for multimodal cancer immunotherapy.
4.1. Combination with adjuvants or vaccines
Antigen presentation, as the first stage of the immune response, is
considered as the initiation of the immune response [128]. However, the
efficiency of antigen presentation alone from the stimulation of the ICD
is sometimes not enough to induce intense immunotherapy. Combining
ICD with vaccines or adjuvants might reinforce the generation of
immunogenic fragments or other danger signals in tumor tissues [131,
132]. Cytosine-phosphate-guanine (CpG), as a Toll-like receptor 9
(TLR9) agonist, can provoke the host immunity and stimulate cytokine
secretion by priming immature DCs. Recently, CpG has been proved as a
remarkable immune-adjuvant against solid tumors in clinical studies
10
Biomaterials 282 (2022) 121433
[131,133]. For example, Im et al. designed a hypoxia-triggered meso­
porous silica nanocarrier (CAGE) [131]. In the nanosystem, Ce6 was
conjugated within the mesoporous silica nanoparticle decorated by Azo
linker, and then the adjuvant (CpG) was loaded into the CAGE complex
via electrostatic interaction [131]. Once CAGE was in a hypoxic condi­
tion within tumor tissues, CpG could be rapidly released by the cleavage
of the Azo linkers [131]. Under local NIR light irradiation, ROS-induced
DAMPs from B16⋅Mo5 cells and the released CpG simultaneously
recruited DCs and promoted the maturation of DCs to present antigen
[131]. As results, a robust antitumor response was evoked and a large
number of CTLs infiltration at tumor site was observed in the B16⋅Mo5
tumor bearing mice treated with CAGE + laser [131]. Moreover, Yang
et al. also developed a multipurpose polymersomal nanoformulation
encapsulating HPPH and Dox [132]. Interestingly, the chimeric
cross-linked polymersome (CCPS) with primary and tertiary amines
could act as an adjuvant, together with TAAs released from MC38 cells
by PDT to enhance the level of DCs recruitment [132]. In vivo, high level
of mature DCs in lymph node and CTLs at tumor site were observed due
to the “in situ vaccine” acted by CCPS/HPPH/Dox under NIR light irra­
diation [132]. It followed that the combination of ICD and adjuvant
exerted potent PDT-synergized immunotherapy, leading to the highly
effective suppression on primary and distant tumors in MC38
tumor-bearing C57BL/6 mice [132].
In addition, the effective combination of ICD and vaccine could also
enhance immune stimulation and further potentiate immunotherapy.
Recently, Cheng et al. synthesized a chimeric peptide PpIX-PEG8-
KVPRNQDWL, which could self-assembly into NPs (PPMA) with high
drug loading rate [134]. In this nanosystem, the melanoma specific
antigen (KVPRNQDWL) peptide could activate the infiltration of specific
cytotoxic T cells into tumor tissues and synergistically amplify
PDT-based immunotherapy against malignant melanoma [134]. To
further elevate the level of antigen presentation, Xu et al. constructed a
biodegradable mesoporous silica nanoparticle (bMSN) nanoplatform
with the co-loading of neoantigen-based vaccine, CpG oligodeox­
ynucleotide adjuvant, and photosensitizer Ce6 [135]. Compared with
single PDT, vaccine, or adjuvant, the multifunctional nanomaterial
system recruited more tumor-infiltrating cytotoxic T-cells and exhibited
a more potent antitumor efficacy on primary and contralateral MC-38
tumors in multiple murine models of bilateral tumor [135]. Therefore,
the multiple-stimuli design offered a promising approach for eliciting
potent antitumor immune response [135].
4.2. Combination with checkpoint blockade
Immune checkpoints are functional molecules that negatively regu­
late the host immune response under physiological conditions, which
could maintain the host immune tolerance and reduce the damage to
tumor tissues in the process of immune response [136,137]. One of the
mechanisms of tumors escaping immune attack is to down-regulate the
immune response through immune checkpoints, which modulate almost
each step of the tumor immune cycle. Especially for tumor elimination
stage, once the PD-1 receptor expressed on the surface of immune T cells
combines with the PD-L1 ligand expressed on the surface of tumor cells,
a negative control signals will be generated to induce T cells entering
into the resting state [128]. Following the conveyed signal, the prolif­
eration of CD8+ T cells in lymph nodes and the recognition of tumor cells
at tumor site will be reduced, and eventually result in the occurrence of
immune escape. The combination of PDT and anti-PD-1/PD-L1 antibody
could effectively unshackle the immunosuppression of immune check­
point PD-1/PD-L1 and enhance immune response against tumor [125,
138–140].
Recently, there have been many studies about the application of
PDT-mediated ICD induction combined with anti-PD-1/PD-L1 antibody
[125,138–140]. Duan et al. designed nontoxic core-shell Zn-pyr­
ophosphate (ZnP) NPs loaded with the photosensitizer pyrolipid
(ZnP@pyro) [139]. Under NIR light irradiation, the ZnP@pyro could
S. Zhang et al.
both kill tumor cells and trigger the ICD-based host immune response
[139]. In vivo results, ZnP@pyro-mediated PDT not only successfully
inhibited the primary 4T1 tumor but also effectively prevented the lung
metastasis [139]. Furthermore, the combination of ZnP@pyro-mediated
PDT and anti-PD-L1 antibody could sensitize tumor cells to effector T
cells, enhance the inhibition of primary 4T1 tumors and simultaneously
suppress the growth of non-laser distant 4T1 tumors in both 4T1 and
TUBO bilateral syngeneic mouse models [139]. Except for large­
–molecule PD-1/PD-L1 antibodies, small-molecule PD-1/PD-L1 in­
hibitors have also been widely investigated recently [130]. BMS-202, a
small-molecule PD-1/PD-L1 inhibitor developed by BMS, could prevent
the PD-1/PD-L1 interaction and enhance immunotherapy [130]. Zhang
et al. constructed a co-assembly nanoplatform of Ce6 and BMS-202 to
accomplish the synergistic effect between PD-1/PD-L1 pathway and PDT
[130]. Ce6 and BMS-202 could assemble into NPs without other carrier
materials by one-step nanoprecipitation method. Due to the high drug
loading, Ce6/BMS-202 NPs exhibited highly effective inhibition on
primary tumor, and concurrently caused ICD of 4T1 tumor cells with
CRT exposure under NIR light irradiation. Moreover, Ce6/BMS-202 NPs
mediated combination therapy of ICB and PDT displayed significant
suppression on distant tumor with efficient maturation of DCs and
infiltration of CTLs cells into the 4T1 tumors. More importantly, the
combination therapy of PDT-based ICD and PD-L1 blockade was able to
successfully prevent lung metastasis and inhibit cancer relapse, making
a tumor prophylactic vaccination effect [130].
Another strategy to block PD-1/PD-L1 is to genetically regulate the
PD-1/PD-L1 pathway via RNA interference (RNAi) [86,141]. Wang et al.
developed an acid-sensitive cationic micelleplex by integrating photo­
sensitizer (PPa) and siRNA [86]. When the micelleplex was caught in the
acid condition in tumor cells, both PPa and siRNA were rapidly released,
and abundant ROS were generated under NIR irradiation [86]. The
released siRNA specifically suppressed PD-L1 pathway and modulated
immune tolerance via silencing the expression of PD-L1 on the surface of
tumor cells [86]. In a B16–F10 melanoma xenograft tumor model, the
combination of PDT and PD-1/PD-L1 block showed a more potent
immunotherapeutic effect on tumor growth, and the lung metastasis was
well suppressed [86]. In addition, Liu fabricated a CaCO3/MnO2-based
nanoplatform with TME responsive biodegradable properties to enhance
PDT and strengthen PD-L1 blocking immunotherapy [142]. The NPs
loaded with ICG and siRNA (Mn@CaCO3/ICG@siRNA) could relieve the
hypoxic environment and accomplish the degradation of carrier by
consuming H+ and H2O2 in tumor cells [142]. Due to the oxygen sup­
plement, the enhanced PDT promoted the release and presentation of
TAAs to induce intense ICD of tumor cells and activated the effector T
cells [142]. With the help of siRNA, the activated effector T cells
effectively recognized and killed cancer cells, achieving synergistic ef­
fect between PDT and PD-L1 blocking immunotherapy in the Lewis lung
cancer-model [142].
In addition to PD-1/PD-L1 checkpoint, CTLA-4 overexpressed on
activated CD4+ and CD8+ T cells, has a high homology with the co-
stimulating molecular receptor (CD28) on the surface of T cells. Anti-
CTLA-4 can block inactivation of effector T cells and CTLA-4-
dependent immune evasion [92,129]. Some researchers have demon­
strated that combining PDT-inducted ICD with CTLA-4 checkpoint
blockade could improve the synergistic immunotherapy [92,129]. To
enhance the combination effect, Xu et al. designed Ce6-based image-­
guided PDT in combination with PD-L1 and CTLA-4 dual checkpoint
blockade [129]. They found that Ce6 + immunoglobulin G could
assemble into nanostructure Chloringlobulin with the assist of poly­
vinylpyrrolidone (PVP) [129]. Subsequently, they utilized the αPD-L1 or
anti-CTLA-4 antibody (αCTLA-4) to prepare αPD-L1 Chloringlobulin,
αCTLA-4 Chloringlobulin and αPD-L1αCTLA-4 Chloringlobulin, and
further demonstrated the advantages of double-blocking immune
checkpoint over single-blocking immune checkpoint, which could elicit
robust host antitumor immunity and a persistent immune memory
against tumor rechallenge in GL261 orthotopic tumor-bearing mice
11
Biomaterials 282 (2022) 121433
[129].
T cells will stop proliferating once exposed to low concentration of
tryptophan. IDO, as a neo-immune checkpoint protein, can discontinue
the activation of T cells by degrading tryptophan [143,144]. Both IDO
expressed in the tumor cells and some APCs can mediate the immune
escape of the tumor by inhibiting the proliferation of T cells [143,144].
IDO inhibitors can regulate the immunosuppressive TME and promote
the activation and proliferation of effector T cells [145,146]. The com­
bination of PDT and IDO inhibitor can significantly enhance the
immunotherapeutic effect [91,105,126,128,147,148]. For example, NPs
loaded with HPPH and IDO inhibitor indoximod (IND) could induce ICD
of tumor under NIR light irradiation. The proliferation of CD8+ T cells
was promoted with the help of IND, resulting in an enhanced antitumor
immunotherapy in 4T1 tumor-bearing mice [91]. Song et al. synthesized
a caspase-responsive chimeric peptide PpIX-1MT by integrating photo­
sensitizer PpIX with IDO inhibitor 1-methyl-tryptophan (1 MT) [50].
The PpIX-1-mt could self-assemble into NPs and target to tumor tissue by
the enhanced penetration retention (EPR) effect [50]. Upon NIR light
irradiation, the PpIX-1MT NPs generated ROS to induce the ICD of CT26
tumor cells following with high CRT exposure and trigger the immune
response [50]. Then, the subsequently released 1 MT via the cleavage of
the caspase could improve the activation efficiency of CD8+ cells [50].
Consequently, a cascaded synergistic therapy inhibited both primary
and lung metastasis tumor successfully in CT26 tumor-bearing mice,
which might provide a promise for preventing tumor recurrence and
metastasis clinically [50]. In addition to IND and IMT, some other small
molecule IDO inhibitors such as INCB24360 and NLG919 were also used
to strengthen immune response [105,126]. Recently, nanoassemblies
with multiple therapy modalities have attracted more attention from
researchers. Li et al. constructed a three-in-one immunotherapy nano­
platform by a cascade enhancement on the three stages of immuno­
therapy [128]. The multifunctional nanoplatform was composed of
Ce6-conjugated HA (HC) with negative charge, dextro-1-methyl tryp­
tophan (1-mt)-conjugated polylysine (PM) with positive charge and
anti-PD-L1 monoclonal antibodies (aPD-L1) (Fig. 9) [128]. After accu­
mulation in tissues, the aPD-L1@HC/PM NPs firstly underwent charge
reversal due to the overexpressed HAase, and aPD-L1 was released
during this process. The positive charged nanoassemblies were easier to
be endocytosed into cells, and could release the Ce6 and 1-mt under the
action of cathepsin B. Under NIR light irradiation, Ce6 produced cyto­
toxic ROS to induce robust ICD with higher CRT exposure on B16F10
cells [128]. Meanwhile, IDO inhibitor 1-mt could enhance the activation
and proliferation of effector T cells, and aPD-L1 facilitated T cells
eliminating tumor cells. As a result, the three-in-one immunotherapy
nanoplatform not only inhibited the growth of primary tumor but also
prevented the distant tumor growth and lung metastasis, thereby per­
forming an excellent cascade-amplifying immunotherapy effect in
B16F10 tumor-bearing mice [128].
In addition, the inhibitors or agonists of OX40 or TIM-3 have
received considerable attention in the field of immunotherapy. OX40
(CD134, TNFRSF4) was originally defined as a T cell activation marker,
but it was later found to be a member of the co-activating NGFR/TNFR
superfamily [149]. OX40 is mainly expressed on the activated effector T
cells, regulatory T cells (Tregs), NK cells and neutrophils. Anti-OX40
strategies have been proved to improve the immune system responses
via multiple routes, mainly including: (i) increasing the survival and
expansion of effector and memory T cells; (ii) promoting the secretion of
cytokines, such as IL-2, IL-4, IL-5 and IFN-γ; and (iii) inhibiting the
immunosuppressive Tregs [149]. However, anti-OX40 agonists alone
could not yield satisfactory therapeutic outcomes, especially the meta­
static tumors. To address this challenge, combination of anti-OX40 ag­
onists with other therapeutic modalities have been explored to enhance
the effectiveness of immunotherapy [150,151]. For instance, Alvim
et al. found that the combination of PDT with PD-1 inhibitor and OX40
agonist significantly enhanced antitumor immune response [152]. In
mice allografted with MB-49 UTUC cells, the combination therapeutics
S. Zhang et al.
Fig. 9. The assembly and step-by-step release behavior f aPD-L1@HC/PM NPs (A) Assembly strategy for aPD-L1@HC/PM NPs. (B) Illustration of the step-by-step
detached release behavior of aPD-L1, Ce6, and 1-mt and the immunotherapy capability via the cascade-amplifying cancer-immunity cycle [128]. Reprinted with the
permission from (Li et al., 2019). Copyright (2019), American Chemical Society.
demonstrated distinct advantages over the single treatment in terms of
tumor suppression, metastasis inhibition and immune response [152].
Unlike other immune checkpoint molecules, TIM-3 was found to be
specifically upregulated in CD4+ helper T cell 1 (Th1) and CD8+ cyto­
toxic T cells [153]. After being activated by its ligand galectin-9, TIM-3
inhibits the activity of effector T cell, resulting in T cell depletion in
tumors [154]. Furthermore, it has been found that animals with high
TIM3 expressions usually show resistance to anti-PD-1 therapy [155].
Therefore, a combination of anti-TIM3 and anti-PD-1 strategies repre­
sents a promising tumor immunotherapy [156,157]. For instance,
Huang et al. developed a liposome encapsulated with ICG that could
eradicate the primary tumors upon NIR light irradiation [157]. When
combined with PD-1/TIM-3 blockade, the combination strategy effec­
tively suppressed the distant tumors in two colon cancer animal models
(CT26 and MC38) [157].
4.3. Combination with other therapeutics
In addition to the combinations mentioned above, there are other
alternative combination approaches for enhancing PDT-synergized im­
mune response [59,127,158]. Imatinib (IMT), a novel inhibitor of Treg
cells activation, could readily cut down Treg cells-mediated immuno­
suppressive function by inhibiting the expression of transcription factors
STAT3, STAT5 and Foxp3 [127]. Ou et al. designed a pH-sensitive and
layer-by-layer hybrid nanoassembly loaded with IR-780 and IMT [127].
Firstly, the GITR antibody with the function of targeting to Treg cells
was connected to PLGA [127]. Subsequently, IMT and IR-780 were
incorporated into this nanosystem, which were further coated with
pH-sensitive polymers [127]. Upon endocytosed into the acid tumor
environment, the designed NPs would release IR-780 and IMT. Under
NIR light irradiation, IR-780-mediated PDT could induce the release of
TAAs and DAMPs, promote DCs maturation and antigen presentation to
T cells [127]. Meanwhile, the introduction of IMT disrupted the
immunosuppressive function of Treg cells, and conclusively induced
tremendous effector T cells towards tumor tissues [127]. As a result, the
combination treatment significantly extended survival of mice and
inhibited the regrowth after therapy in B16BL/6 tumor-bearing mice
12
Biomaterials 282 (2022) 121433
[127].
Sorafenib, a multi-kinase inhibitor, could suppress the immunosup­
pressive cells and potentiate tumor-specific cytotoxic T cell in TME,
performing an augmented antitumor immune response [158]. Sun et al.
designed ROS-responsive NPs (NPs-sorafenib/Ce6) co-loaded with sor­
afenib and Ce6 to enhance antitumor immunotherapy [158]. Under NIR
light irradiation, large quantities of cytotoxic ROS were produced,
which induced the apoptosis of tumor cells and the release of TAAs, from
dying tumor cells, and accelerated the release of intratumoral sorafenib
[158]. The released sorafenib subverted the immunosuppressive
microenvironment and enhanced the antitumor immune response
induced by PDT, improving the infiltration of cytotoxic CD8+ T cells in
tumor tissues and finally furnishing a potent suppression of 4T1 tumor
elimination and metastasis [158]. Moreover, the measure results of
tumor-infiltrating CD8+ demonstrated PDT-based combination with
sorafenib could induce strong and long-lasting antitumor immune
response against 4T1 tumor-bearing BALB/c mice [158].
5. Conclusions
Cancer immunotherapy is currently one of the most promising
treatment modalities, but its application is limited by its low immune
response and potential side effects. Non-invasive and spatiotemporal
PDT can induce ICD of tumor cells and further stimulate immune
response. Therefore, effective PDT enables to not only kill tumor cells
but also reverse the immunosuppressive TME, and further achieve a
desired synergy with other immunotherapeutics. The application of
biomedical nanotechnology in PDT and PDT-based ICD induction has
shown many advantages, such as improving the physicochemical
properties of PSs, extending the blood circulation time, facilitating
tumor-targeting accumulation and enhancing PDT-induced ICD. More­
over, the integration of PSs with various nanomaterials can not only
overcome challenges of PDT, such as hypoxia, ACQ effect, poor pene­
tration and targeting ability, but also enhance the induction of ICD and
immunotherapy based on PDT through collaborative delivery strategy.
Among the diverse nano-vehicles, self-assembled nanoplatforms of small
molecules have exhibited unique advantages of high drug loading
S. Zhang et al.
capacity, carrier-free self-delivering feature, tumor-specific drug acti­
vation or release and high security, which hold great promise for clinical
applications in the future. In this review, we outlined recent advanced
photodynamic nanotherapeutics to induce ICD of tumor cells and
potentiate cancer immunotherapy following three aspects: (i) the
emerging photodynamic nanotherapeutics for ICD induction; (ii) PDT-
based combination strategies for potentiating ICD induction; (iii)
multimodal cancer immunotherapy based on photodynamic ICD
induction.
Although the rapid development of PDT-synergized immunotherapy,
some limitations and challenges associated with PDT and immuno­
therapy remain to be solved. Firstly, the clinical application scopes of
PDT and immunotherapy have certain boundedness for cancer patients,
since PDT is still restricted to the treatment of epidermal tumors or tu­
mors near the skin. Moreover, the specificity and immunosuppression of
tumors can also result in great discrepancy of therapeutic outcomes and
further limit the application of immunotherapy. Secondly, the mass
production and safe application of diverse biomaterials are still great
challenges. Finally, the immune response against tumors is an extremely
complicated process, in which the interruption of any step will weaken
the effect of anti-tumor immunotherapy. In the future, it is necessary or
rationally designing more effective nanotherapeutics to acquire desir­
able antitumor immunotherapy.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
This work was financially supported by the National Nature Science
Foundation of China (No. 82161138029), the Liaoning Revitalization
Talents Program (No. XLYC1907129), the Excellent Youth Science
Foundation of Liaoning Province (No. 2020-YQ-06), and the China
Postdoctoral Science Foundation (No. 2020M670794 and No.
2021MD703858).
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