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Engineering immunogenic cell death with nanosized
drug delivery systems improving cancer immunotherapy
Wenlu Yan1,2,3, Tianqun Lang1,3, Xianrong Qi2 and Yaping Li1,3
Many anti-cancer therapies can induce or enhance the
immunogenic cell death (ICD), a process that releases damage-
associated molecular patterns (DAMPs) to prime antigen
processing and presentation necessary for successful cancer
immunotherapy. However, the clinical potential of these
therapies, especially the chemotherapy, is limited by serious
systemic side effects, because of their non-specific
accumulation out of the tumors. Nanosized drug delivery
systems (NDDSs) can improve the specificity of anti-cancer
therapies, which enhance ICD in the tumor while alleviating
toxicities. In this review, we summarize recent progress of ICD-
inducing NDDSs with a focus on their enhanced safety and
efficacy for cancer immunotherapy.
Addresses
1
State Key Laboratory of Drug Research & Center of Pharmaceutics,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
501 Haike Road, Shanghai 201203, China
2
School of Pharmaceutical Sciences, Peking University, 38 Xueyuan
Road, Beijing 100191, China
3
School of Pharmacy, University of Chinese Academy of Sciences,
Beijing 100049, China
Corresponding author: Li, Yaping (ypli@simm.ac.cn)
Current Opinion in Biotechnology 2020, 66:36–43
This review comes from a themed issue on Tissue, cell and pathway
engineering
Edited by Li Tang, Peng Xu and Haoran Zhang
For a complete overview see the Issue and the Editorial
Available online 13th July 2020
https://doi.org/10.1016/j.copbio.2020.06.007
0958-1669/ã 2020 Elsevier Ltd. All rights reserved.
Introduction
Immunotherapy revolutionizes the field of cancer therapy,
which normalizes or enhances immune surveillance to fight
against cancer [1]. Several immunotherapies including
immune checkpoint blockade (ICB) and T-cell transfer
therapy have been used in the clinic. However, low response
rate and severe immune-related side effects (irSEs) are two
major challenges for cancer immunotherapy [2].
The low response rate of immunotherapy is likely associ-
ated with reasons such as low immunogenicity of tumor,
poor immune cell infiltration and immunosuppressive
Current Opinion in Biotechnology 2020, 66:36–43
tumor microenvironment (ITM) [3]. One potential strat-
egy to address these issues is promoting immunogenic
cell death (ICD), a type of cell death releasing neoanti-
gens as well as damage-associated molecular patterns
(DAMPs) including calreticulin (CRT), high mobility
group box 1 (HMGB1), heat shock protein (HSP) and
adenosine-5’-triphosphate (ATP) [4]. CRT binding to
CD91 receptor promotes phagocytosis together with
HSP. Recruitment and activation of dendritic cells
(DCs) are advanced after the recognition of ATP by
P2X7 receptor and HMGB1 by Toll-like receptor
(TLR). Tumor-associated antigens (TAA) are then
cross-presented to CD4+ and CD8+ T cells by matured
DCs, triggering adaptive immune responses against
tumors and turning tumor microenvironment (TME) to
immunogenic state [5]. In summary, ICD-induction pro-
vides a lymphocytes-enriched TME for enhancing immu-
notherapy (Figure 1a).
Meanwhile, non-specific deposition of ICD inducers
or other immunotherapy agents is likely to cause irSEs
[6]. Encouragingly, nanosized drug delivery systems
(NDDSs) have shown great potential in addressing these
challenges with their abilities of improving the pharma-
cokinetic and bio-distribution profiles of drugs to accu-
mulate in tumors via the enhanced permeability and
retention (EPR) effect and decreasing the off-target
adverse effects [7,8]. NDDSs are also promising in the
combined cancer therapy owning to their capacity of
co-delivering drugs [9].
In this review, we will summarize the NDDSs-based
strategies that have been utilized to leverage ICD for
more efficient and safer cancer immunotherapy with a
focus on their design and mechanism of actions
(Figure 1b). Finally, the important contributions and
the possible directions of this field in the future will be
discussed.
Engineering ICD with NDDSs-based therapy
Treatments that can induce or enhance ICD include
chemotherapy, phototherapy and radiotherapy [4].
NDDSs transport ICD-inducing agents and immunother-
apy drugs to tumor sites together or separately, which
reduce adverse reactions and improve efficiency
(Figure 1c).
NDDSs-based chemotherapy
Some chemotherapeutics such as oxaliplatin (OXA) and
doxorubicin (DOX), as type Ⅰ ICD inducers, act on targets
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 Engineering ICD with NDDSs for immunotherapy Yan et al. 37

Figure 1

(a) ICD improving different immunotherapies

(b) ICD-inducers deliveed by nanoplatforms improving immunotherapy (c) Different administration strategies

Current Opinion in Biotechnology

ICD-engineering treatments based on NDDSs improving immunotherapy.

Chemotherapy (CT), phototherapy (PT) and radiotherapy (RT) act on different targets (such as DNA, functional proteins or endoplasmic reticulum
(ER)) to induce ICD [10] ((a), left panel). Tumor cells undergoing ICD release DAMPs which activate DCs and T cells, improving the anti-tumor
effect of immunotherapy [4] ((a), middle panel). Three major immunotherapies are discussed in this review ((a), right panel). ICD inducers delivered
by functional nanoplatforms promote the efficiency and safety of immunotherapy [11] (b). ICD inducers and immunotherapy agents are targeted
delivered by nanoplatforms together or sequentially to tumor tissues and achieve tumor inhibition by triggering immune responses (c).

unrelated to endoplasmic reticulum (ER) such as DNA or
functional proteins to induce apoptosis and collateral ER
stress effects [10]. Nanoparticles-encapsulated ICD indu-
cers generated stronger anti-tumor effect than non-ICD
inducers or free ICD inducers [11], indicating that
NDDSs-based chemotherapy was a feasible strategy to
improve immunotherapy.
Combined with ICB
The low response rate due to limited T cell activation and
infiltration in tumor is a main barrier of ICB. Chemotherapy
inducing ICD promotes the infiltration of CD8+ T cells, but
upregulates the expression of PD-L1 through NF-kB
signaling [12]. When combining these two complementary
therapies, anti-tumor effect will be greatly improved. Kuai
et al. proposed a method to deliver DOX to tumors
with a pH-sensitive high-density lipoprotein nanodisc
(sHDL-DOX), increasing the intracellular uptake of
DOX by 2.8 times compared with free DOX injection
[13]. After sHDL-DOX and anti-PD-1 therapy, 88% mice’s
tumors were eradicated, whereas anti-PD-1 monotherapy
could not control tumor growth of mice. The work of Zou
et al. demonstrated similar results, in which catalase (CAT)
and DOX were co-delivered via a biomimetic nanoplatform
[14]. DOX triggered ICD, while CAT catalyzed in situ
H2O2 to relieve hypoxia of TME and downregulate the
expression of PD-L1 of tumor cells, thus creating an
enabling environment for ICB.

www.sciencedirect.com Current Opinion in Biotechnology 2020, 66:36–43

38 Tissue, cell and pathway engineering
Since systemic ICB may cause irSEs, tumor-localized
inhibition of PD-L1 is preferential. Su et al. utilized
copolymer of azide-terminated polyethylene glycol
(PEG) and poly-aspartic acid to assemble a pH-sensitive
micelle with paclitaxel (PTX) in the core, which was then
decorated with anti-PD-1 antibodies (aPD-1) via matrix
metalloproteinase-2 (MMP-2) -sensitive peptide linker
and PEG chain [15]. The micelle became positively
charged after PEG shedding and aPD-1 releasing in
weakly acidic (pH  6.5) and enzyme-rich TME, promot-
ing the internalization of tumor cells. PTX was finally
released in lysosomes (pH  5.0) and then induced ICD
of tumor cells. This space-specific administration strategy
achieved synergistic anti-tumor profit, providing a feasi-
ble idea for the co-delivery of ICB drugs and ICD
inducers (Figure 2). The siRNA for PD-L1 knockdown
or JQ1 for PD-L1 downregulation was co-delivered with
ICD inducers by nanocarriers, leading to successful anti-
tumor chemo-immunotherapy as well [16,17].
Combined with IDO inhibitor
It has been confirmed that interferon-g (IFN-g) secretion
boosted by chemotherapeutics promotes overexpression of
indoleamine 2,3-dioxygenase (IDO), a key factor leading to
ITM and immune escape. The IDO also promotes the
proliferation of regulatory T cells (Tregs). Inhibitors of
IDO are thus able to reverse ITM and elicit the immune
response with ICD. Inspired by this idea, Feng et al. con-
structed a prodrug nanoparticle with PEG-grafted OXA
Figure 2
Smart NDDS achieving space-specific administration of aPD-l and PTX.
MMP-2 and pH dual-sensitive NDDS co-delivered aPD-l and PTX, releasing aPD-l in weakly acidic and enzyme-rich TME. PTX induced ICD after
internalization by tumor cells, synergizing with ICB therapy to enhance the killing effect of CD8+ T cells on tumor cells [15].
Current Opinion in Biotechnology 2020, 66:36–43
and homodimer of IDO inhibitor NLG919, with 30-fold
and 5.3-fold higher drug accumulation at the tumor site
than free OXA and NLG919 [18]. Through dual regula-
tion of ITM, the binary prodrug nanoparticle achieved
twofold stronger anti-cancer effect than free NLG919
alone. The nanoparticle with simple preparation proce-
dures is favorable for clinical transformation. Similar
outcomes were shown that co-administration of chemo-
therapeutic agents and IDO inhibitor indoximod (IND)
regressed primary and metastatic tumors [19,20].
Combined with immunopotentiator
Cancer vaccines triggering immune responses are likely
to eliminate tumors. Besides biosafety, personalization of
vaccines and immune tolerance of TME are two barriers
that need to be overcome. In a recent work, curcumin-
loaded polymer nanoparticles with the particle size of
98.73 nm and nanovaccines composed of antigen peptides
and TLR agonists with the particle size of 91.23 nm self-
assembled into hydrogels [21]. Curcumin induced ICD
to turn ‘cold’ tumors into ‘hot’ tumors, and the vaccine
further amplified the immune response. After combined
therapy, the infiltration of CD8+ T cells in tumors was
4.89 and 2.11 times higher than that of nanomedicine and
nanovaccine, respectively.
Adjuvants, as immune enhancers, are expected to be a
new choice for cancer therapy. Cytosine-phosphate-
guanine (CpG) can induce the immune response and
Current Opinion in Biotechnology
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promote the secretion of pro-inflammatory cytokines after
recognition by TLR-9. However, high dose and repeated
administration cause adverse reactions. To address the
problem, Wang et al. developed nanocomposites by con-
necting DOX and CpG-silver nanocluster to MnO2
nanosheets, taking advantage of DOX as bi-functional
modulator for ICD induction and TME transformation to
stimulate cancer immunotherapy of CpG [22]. The tumor
inhibition rate of combined treatment was 95%, 3.9-fold
higher than treatment without DOX.
NDDSs-based phototherapy
Recent studies have shown that phototherapy including
photodynamic therapy (PDT) and photothermal therapy
(PTT) can also induce systemic activity by priming anti-
cancer immunity. As a type Ⅱ inducer, PDT selectively
targets to ER and generates reactive oxygen species
(ROS) through photosensitizer, exposing CRT via PERK
and BAX/BAK signal pathway [5,10]. PTT kills cancer
cells by generating local hyperthermia, leading to release
of TAA without relying on the hypoxic microenvironment
of tumor tissue [23]. With the ability of immune stimula-
tion, phototherapy is thus potential to synergize with
immunotherapy to achieve comprehensive suppression
of primary and metastatic tumors.
Combined with ICB
Promotion of intratumoral infiltration of cytotoxic T
lymphocytes (CTLs) improves the efficacy of ICB ther-
apy. Wang et al. combined indocyanine green (ICG, a
Figure 3
Nanoparticles capturing tumor antigens to improve immunotherapy.
Nanoparticles capture tumor antigens released from primary tumor cells undergoing ICD and transport them to DCs. Combining this strategy with
aCTLA-4 [28] or aPD-1 [29], suppression of metastatic tumor can be achieved.
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Engineering ICD with NDDSs for immunotherapy Yan et al. 39
photosensitizer) with aPD-L1 through a TME-sensitive
nanocarrier, promoting DCs maturation and CTLs infil-
tration after laser irradiation [24]. Assisted by combining
therapy, over 80% 4T1 tumor-bearing mice survived until
70 days, whereas mice treated aPD-L1 all died within
45 days.
Besides co-transportation, the lipid encapsulating the
Zn2+ ions coordinated with pyrophosphate as the core
and the lipid layer loaded with photosensitizer assembled
the nanoparticles, which preferentially accumulated in
tumor owing to long circulation capacity with blood
circulation half-life of 14.5 hours. Then the radiation
boosted release of TAA, enabling complete tumor eradi-
cation with subsequent anti-PD therapy [25].
PTT inducing ICD maintains the immunogenic micro-
environment for ICB therapy. Under infrared light irra-
diation, nanoplatforms loaded with photothermal agent
and TLR receptor agonist [26], tubulin-stabilizer, or
stimulator of interferon genes agonist [27] triggered spe-
cific immune response and achieved long-term tumor
suppression when combined with ICB therapy.
Another innovative study reported a multi-functional
nanoparticle formed with light absorber, photosensitizer
and DSPE-PEG-maleimide, with the ability of capturing
the TAA induced by thermal radiation and transporting
them to DCs [28] (Figure 3). From primary induction to
accomplishing chain processing of the antigens, this
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Current Opinion in Biotechnology 2020, 66:36–43
40 Tissue, cell and pathway engineering
strategy provides a new insight for improving the immune
response induced by ICD.
Combined with IDO inhibitor
Physical therapy, including phototherapy, can also upreg-
ulate IDO. To address this issue, Gao et al. prepared a
TME-sensitive prodrug vesicle for specific delivery of
NLG919 and photosensitizer pheophorbide A (PPa) [30].
ICD induction by PDT combined with IDO inhibition
provoked 34.4  1.3% maturation of DCs and increased
the intratumoral infiltration of IFN-g+ CD8+ T cells by
30-fold higher than the control group. This work
addressed the negative feedback regulation of immuno-
suppression caused by PDT. Moreover, a nanovesicle
assembled from block copolymer polyethylene glycol-
b-cationic polypeptide not only carried photosensitizer
and IND, but also induced ICD itself [31]. Through the
cytotoxicity of ROS, immune activation, and regulation of
ITM, PDT immunotherapy inhibited tumor growth with-
out causing obvious systemic toxicity, while free IND had
minimal inhibitory effect on the tumor. In addition, a
redox-responsive disulfide nanoliposome activated
photoactivity by more than 100-fold without photosensi-
tizer and promoted anti-cancer treatment synergistically
when encapsulating IND [32].
Combined with immunopotentiator
To solve the problems of limited light penetration depth
of PDT and low efficiency of photosensitizer loading, a
large-pore mesoporous-silica-coated upconversion nano-
particle was designed with the capability of loading
photosensitizers (12.28 wt%) and tumor cell fragments
as autoantigens (39.7 wt%) [33]. During PDT, endoge-
nous and exogenous antigens synergistically promoted
the proliferation and activation of T cells. Since intact
cells were more immunogenic than cell fragments, Wang
et al. used the tumor-penetrating peptides to assemble
nanofibers and transform into hydrogels. Then tumor
cells attached ICG and JQ1 were encapsulated [34].
Local injection delayed 48.1% of the tumor recurrence
and eliminated 83.3% of metastatic tumor, showing the
potential of this strategy in personalized immunotherapy.
High local hyperthermia predicts better outcome of PTT
but also causes damages to healthy tissues and immune
cells in the TME, leading to immune suppression. Chen
et al. demonstrated that mild hyperthermia could induce
durable immune memory and delay tumor growth using
NDDSs loaded with TLR agonists, proving that balanc-
ing tumor eradication and immune cell priming was
critical for an in situ vaccine [35].
NDDSs-based radiotherapy
Radiotherapy is the mainstream external treatment
for cancer by primarily disrupting the chemical bonds
between the bases in DNA [36]. The generation of ROS
induced by ionizing radiation medicates the upregulation
Current Opinion in Biotechnology 2020, 66:36–43
of adhesion molecule and E-selectin to boost immune cell
recruitment and inflammatory cytokine signaling. The
chemokine gradient attracts effector T cells to irradiated
tumor with the promotion of vascular cell adhesion mol-
ecule (VCAM)-1, and the increased expression of major
histocompatibility complex class Ⅰ (MHC-I) on the tumor
improves recognition and killing by immune system.
Effector T cells kill cancer cells through Fas-induced
apoptosis or cytotoxic granules, releasing new TAA and
thus boosting the abscopal effect medicated by immune
response [37,38].
Low-dose hypo-fractionated radiation reprograms macro-
phages to M1 phenotype and induces more effective
ICD-based antigen release than single-dose radiotherapy.
High-atomic-number nanoparticles with high X-ray
absorption coefficients, as novel radiosensitizers, contrib-
ute to the local damage to tumor cells of radiotherapy.
Hafnium (Hf)-based nanoscale metal-organic frameworks
which could promote ROS diffusion, were injected
intratumorally followed by low-dose hypo-fractionated
radiation, extinguishing both the primary irradiated and
secondary unirradiated tumor combined with aPD-L1 or
IDO inhibitor [39,40].
The effectiveness of radiotherapy depends on the con-
centration of oxygen. Chen et al. designed a biocompati-
ble nanoparticle with hydrophilic CAT in the core and
hydrophobic immune adjuvant R837 in the poly(lactic-co-
glycolic) acid (PLGA) shell through double emulsification
method [41]. CAT relieved hypoxia of tumor tissue and
adjuvant promoted the recognition of tumor antigens by
immune cells under X-ray radiation. When combined
radiotherapy with aCTLA-4, 60% of mice achieved
60-day survival, which indicated the nanoparticle was
a feasible strategy for broadening the application of
radiotherapy.
Not only could nanoparticles mediate the production of
tumor antigens, but also capture and deliver antigens
produced by radiotherapy to DCs to enhance cancer immu-
nity. Min et al. decorated nanoparticles formulated from
PLGA with amine polyethylene glycol, 1,2-dioleoyloxy-3-
(trimethylammonium) propane or maleimide polyethylene
glycol for binding to TAA through different mechanisms, so
as to promote antigen presentation and trigger a successful
adaptive immune response [29]. This approach is com-
patible with clinical immunotherapy treatment options,
and thus is of great translation potential.
Furthermore, to enhance the efficacy of radiation, opti-
mization of nanoparticles to maximize cellular uptake is
highlighted [42]. Notably, attention should also be paid
to timing and sequencing of radiotherapy and ICB,
since radiation-induced acute increase of TAA produc-
tion and tumor infiltrating lymphocytes only lasts for a
few days [43].
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NDDSs-based combinatorial regimens
Combination use of chemotherapy and physical therapy
(including phototherapy and radiotherapy) with different
patterns of released DAMPs may complement with each
other and exhibit stronger ICD. One requisition to
achieve synergistic effect is to deliver different drugs
into the tumor and release them in a controlled manner.
NDDSs with multifunctionality, can fulfil this after
optimization.
The most commonly used strategy is the combination of
phototherapy and chemotherapy. Feng et al. reported a
two-in-one nanoparticle loading ICG to medicate PDT
and PTX to reverse ITM efficiently without excipients
(termed as ISPN) [44]. It could target to tumor tissue and
secrete ATP after laser irradiation by twofold higher than
that of various control groups, indicating a more effective
ICD induction. The combination treatment of ISPN with
aPD-L1 caused a significant immune response against
tumor growth and metastasis (Figure 4). Other studies
demonstrated that PDT and chemotherapy cumulatively
induced ICD as well, delaying the growth of primary
tumors cooperated with aPD-1 or aCD47 [45,46].
Besides PDT, the combination of chemotherapy and
PTT also facilitated the immune response, providing
enough exposure of TAA for ICB therapy [47].
Several studies have indicated that NDDS-based
chemotherapeutics can exacerbate DNA double-strand
damage caused by radiotherapy with unobvious toxicity
Figure 4
Enhancing cancer immunotherapy by ISPN.
Phototherapy and chemotherapy synergistically induce ICD of tumor cells and eliminate immunosuppressive Tregs, inhibiting primary and
metastasis tumors when combined with ICB [44].
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Engineering ICD with NDDSs for immunotherapy Yan et al. 41
[42]. Au et al. designed a DOX-encapsulated nanoparticle
with the capacity of targeting to human leukocyte
antigen-D related (HLA-DR) -overexpressed human
lymphoma cells [48]. ICD induced by DOX and irradia-
tion resulted in the upregulation of HLA-DR, promoting
uptake of nanoparticles and exerting anti-tumor effi-
ciency with a positive feedback pathway. As a result,
about 70% of mice achieved long-term survival after the
concurrent chemo-immuno-radiotherapy.
In order to achieve ICD induction and endogenous IDO
inhibition, PEGylated OXA with ROS-liable thioketal
spacer encapsulated GSH-liable PPa and NLG919 pro-
drug, composing a light-inducible nanocargo (LINC)
[49]. LINC accumulated in tumor tissue and cleaved
PEG under the first near-infrared (NIR) laser. After
tumor cells internalization of LINC, NLG919 reversing
ITM and immune response triggered by the second
irradiation-medicated PDT and OXA eradicated 67%
of the 4T1 tumors. The controllable drug delivery strat-
egy enabled efficient and simple triple combination
therapy.
Discussion and futures directions
Recently, different categories of ICD-manipulating treat-
ments based on NDDSs have been developed and
showed great potential in cancer immunotherapy. The
advantages of NDDSs-based ICD are as followed. Firstly,
it targets to tumor site and induces the release of DAMPs
to act as an in situ vaccine, thereby achieving the effect of
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Current Opinion in Biotechnology 2020, 66:36–43
42 Tissue, cell and pathway engineering
personalized treatment. Secondly, it improves the
infiltration of immune cells to prime immune replete
TME, accomplishing more effective immunotherapy
for tumor suppression while reducing side effects.
Thirdly, the combined delivery of ICD inducers and
immunotherapeutic agents with NDDSs improves their
pharmacokinetic and bio-distribution profiles and
achieves synergistic effects simultaneously.
More investigations are needed to transfer engineering
ICD with NDDSs to clinical application such as devel-
oping highly biocompatible and biodegradable NDDSs.
In addition, how the interaction between nanoparticles
and the immune system can be controlled by tuning the
physicochemical properties of the NDDSs should be
investigated. Furthermore, DAMPs released by ICD
are a double-edged sword that may trigger chronic inflam-
mation and thus promote tumor development [50]. Thus,
combination use of immune modulators is necessary, and
the type, dosage and release kinetic of these modulators
should be carefully tuned. Therapy-resistant microevolu-
tion under selection pressure in cancer is also a hurdle that
ICD-mediating therapies need to address. The properties
of ideal ICD inducers include non-susceptible to drug-
efflux channels and capable of inducing severe focused
ER stress, and so on [51]. For clinical translation, feasible
yet effective NDDSs design is required, which is neces-
sary for large-scale production and quality control. We
believe that with the development of biotechnology and
biological engineering, the relevant mechanisms will be
further clarified. Engineering ICD based on NDDSs will
advance the innovation of cancer immunotherapy.
Conflict of interest statement
Nothing declared.
Acknowledgements
National Natural Science Foundation of China (81871471, 81630052,
81521005, 81690265), Natural Science Foundation of Shanghai
(19ZR1479900), and Key Scientific Research Program of CAS (QYZDJ-
SSW-SMC020) are gratefully acknowledged for financial support.
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