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CHAPTER SEVEN

Challenges and opportunities of nanotechnology in cancer immunotherapy

DaeYong Leea, Kristin Huntoona, Wen Jiangb, and Betty Y.S. Kim

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States

Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX, United States

Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX,

United States

a,c

Contents

1. Background in cancer immunotherapy 197

2. Immunogenic cell death with nanotechnology 199

2.1 Chemotherapy-based ICD 200

2.2 Photodynamic therapy-based ICD 204

2.3 Photothermal therapy-based ICD 207

3. Vaccination with nanotechnology 209

3.1 Peptide vaccine 210

3.2 Tumor cell membrane vaccines 212

3.3 Gene vaccine 214

4. Activation of innate immunity 216

4.1 Macrophage polarization 217

4.2 Phagocytosis activation 221

4.3 NK cell activation with nanotechnology 224

5. T cell activation 225

5.1 Activating T cell immunity with nanotechnology 226

5.2 CAR-T cell therapy with nanotechnology 228

6. Targeting strategies 230

6.1 Lymph node targeting 230

6.2 APC targeting 231

6.3 Tumor targeting 233

7. Perspective 234

References 234

1. Background in cancer immunotherapy

Cancer immunotherapy has revolutionized the field of oncology, providing the

efficient treatments for various malignancies [1]. With the advent of first generation of

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immune checkpoint inhibitors born out successful clinical translation and a new pillar of cancer therapy was established [1]. This major achievement was highlighted by awarding the Nobel Prize in Physiology and Medicine 2018 to Dr. James Allison and Dr. Tasuku Honjo, whom first identified the immune checkpoint blockade in cancer immunotherapy [1].

Targeting immune checkpoint, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)-programmed cell death ligand 1 (PD-L1) axis has been able to overcome the limited therapeutic potency of conventional treatments with satisfactory therapeutic effectiveness in the absence of minimizing side effects [1,2]. However, the benefit of immune checkpoint blockade therapy is limited to only a small portion of patients as the majority of tumors are endowed with local immune tolerance, causing limited therapeutic index [3]. For advanced cancer treatment, chimeric antigen receptor (CAR) T cell-based therapy has been recently devised by genetic engineering and exhibited successful clinical translation in some malignancies

[4]. Despite the outstanding therapeutic effectiveness, CAR-T cell-based therapy has

shown promise only to a minority of cancer patients and showed restricted therapeutic potency in solid tumors [2,4]. Thus, an advanced strategy to safely and efficiently elicit immune responses against cancers and carcinomas remains an important issue to combat in immunooncology.

To broaden the applicability of cancer immunotherapy, various combined treatments have been extensively implemented by harnessing agents that can aid in promoting immunogenicity [5]. For example, the cotreatment of immune checkpoint inhibitors with agents interrupting inhibitory pathways in adaptive immunity has been shown to improve the therapeutic efficacy by establishing elaborate, robust, and long-term adaptive immunity [5]. Despite the enhancement of the therapeutic potency, engaging therapeutic targets at the proper spatial and temporal locations remains a challenge thus requiring advanced technologies to ameliorate the applicability for successful clinical trials.

Recent development in nanotechnology affords new approaches that can not only solve some of the safety issues and concerns but also augment the therapeutic effectiveness by understanding the principles of material and biological sciences [3]. Engineering nanoparticles (NPs) facilitate targeted delivery of the desired therapeutic at the required sites, an extension of the pharmacokinetics of drugs, and visualization of diseased sites for diagnosis [3]. Moreover, some of NPs possess immune-stimulating functions by themselves or it response to stimuli, such as pH, redox-potential, and light [6]. Because of the functionalities and flexibilities of NPs, numerous nanoparticle-based approaches have been intensively devised to unleash innate or adaptive immunity for effective cancer immunotherapy, required for meaningful outcomes in clinical trials [6]. However, to date, many of the candidates have failed to demonstrate satisfactory therapeutic index in clinical models most likely secondary to conditions in tumor microenvironment.

199Challenges and opportunities of nanotechnology in cancer immunotherapy

Fig. 1 Nanotechnology harnessed in cancer-immunity cycle. Nanotechnology can be applied in each step of the cancer-immunity cycle to elicit enhanced antitumor immunity. Immunology orchestrated with nanotechnology boost innate and adaptive immunity, thus enabling tumor-specific T cell priming, expansion, and infiltration into the tumor in several manners.

Ongoing studies should utilize this impetus to develop more advanced and state-of-theart NPs to curtail these limitations in tumor immunotherapy.

In this section, we will introduce how NPs can elicit enhanced antitumor immunity in each step of the tumor-immunity cycle by modulating tumor microenvironments with immune-stimulating conditions (Fig. 1). Additionally, we discuss nanoparticle-based targeting strategies to specific cells or organs that reinforce antitumor immunity while minimizing adverse effects. Finally, we conclude this chapter with a future perspective on cancer immunotherapy.

2. Immunogenic cell death with nanotechnology

The concept of immunogenic cell death (ICD) has been emerging as a novel strategy to unleash innate and adaptive immunity in cancer immunotherapy in which both immunogenicity and adjuvanticity are induced simultaneously [7]. It is evident that

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dying, stressed or injured cells release and/or expose immunostimulatory molecules that act as adjuvant or danger signals for the innate immune systems, coined damageassociated molecular patterns (DAMPs) [7]. During immunogenic cell death, some DAMPs are released from dying cells such as ATP and high mobility group box 1 protein (HMGB1) or can be translocated on the cell membranes such as calreticulin (CRT) and heat shock proteins 90 from the endoplasmic reticulum (ER) [7]. DAMPs and tumorassociated antigens released by various treatments, (i.e., chemotherapy, photodynamic/ photothermal therapy, or radiotherapy) activate innate immune cells and present antigens on their surface, thus recruiting antigen-specific T cells infiltration into the tumor [7]. Some anticancer agents possess the capability to induce not only ICD but apoptosis, which has been shown to aid in cancer immunotherapy [7]. By contrast, non-specific targeting delivery of ICD inducers causes undesirable cytotoxicity and inefficient immunogenicity, thus further demonstrating the need for targeted delivery systems with nanotechnology [8]. Various nanoparticle-based approaches specifically inducing immunogenic cell death have been extensively studied and shown to dramatic improve immunotherapeutic potency (Fig. 2) [8]. Moreover, the combined treatment with immune checkpoint blockade antibodies can achieve superb therapeutic potency by establishing elaborate and robust antitumor immunity [8]. In this chapter, we introduce various types of materials used for nanoparticle preparation and discuss how NPs efficiently induce ICD in diverse manners (Fig. 2).

2.1 Chemotherapy-based ICD

Chemotherapy is the most prevalent and conventional cancer treatment widely used for cancer patients [9]. Recently, various strategies of chemotherapy combined with nanotechnology have been devised to reduce unwanted side effects and also successfully deliver payloads to the therapeutic target—as most current anticancer agents show deficiencies in targeting capability and hydrophobic property [9]. Stimuli-responsive NP approaches enable controlled or sustained release of encapsulated cargos at the desirable time and place, and induction of specific targeting to tumor cells, which can enhance the limited potency of cancer immunotherapy [9]. Many recent efforts to harness stimuliresponsive nanoparticle systems have been shown to drive enhanced immunogenicity. We will discuss several of these approaches triggering nanoparticle-mediated ICD and discuss how NPs elicit enhanced antitumor immunity by promoting the release of DAMPs (Fig. 2).

Doxorubicin (DOX) is a chemotherapy used anticancer agent that can promote the release of DAMPs during the apoptosis process [10]. For example, DOX was appended to liposome-based nanodiscs via an imine bond, a pH-cleavable linker, to safely deliver the payloads into tumor [10] . Nanodisc-mediated DOX delivery translocated CRT on the surface of tumors and accelerated emission of HMGB1 in vitro and in vivo. Thus

201Challenges and opportunities of nanotechnology in cancer immunotherapy

Fig. 2 The general strategy of NP-based ICD induction in cancer immunotherapy. Various NP-based chemotherapy, PDT, and PTT induce ICD by delivering anticancer drugs, producing ROS, or generating heat into the tumor, thus releasing DAMPs and tumor-associated antigens. The released antigens and immunostimulatory molecules promote DC maturation and antigen presentation, which can expand the population of tumor-specific T cells to trigger specific killing into the tumor.

increasing the proportion of CD11c+CD11b+Ly6c+dendritic cells (DCs) as well as the number of presented antigens on their surface compared to the naked DOX treated group [10]. The DC maturation by ICD induction significantly augmented the proportion of interferon-γ (IFN-γ)

CD8+and antigen-specific CD8+T cells, which retarded tumor growth without side effects [10]. Although DOX can trigger immunogenic cell death, the resulting immunogenicity is insufficient to activate antitumor immunity, thus requiring the codelivery strategy to awaken innate immunity [11]. In one example, the codelivery of icaritin and DOX addressed the limitation of low immunogenicity by accelerating the release of DAMPs [11]. The role of icaritin in this study was the upregulation of mitophagy, which highly emitted ATPs to the cytosol, thereby recruiting and activating antigen-presenting cells (APCs) [11]. The codelivery of icaritin and DOX using polyethylene glycol (PEG)-poly(lactic acid-co-glycolic acid) (PLGA)-based NPs was capable of modulating tumor microenvironments to an immune-activating mode

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by increasing the population of tumor-infiltrating CD4+and CD8+T cells activated DCs along with reducing that of M2 macrophages, regulatory T cells (Tregs), and myeloidderived suppressor cells (MDSCs) without side effects, thereby eliminating the established hepatocellular tumor [11]. Moreover, immunosuppressive cytokines, CdC motif chemokine ligand 2 (CCL2), transforming growth factor β (TGF-β), interleukin (IL)-4, IL-6, and IL-10, were diminished while immunostimulative cytokines, IFN-γ, tumor necrosis factor α (TNF-α), and IL-12 were upregulated [11]. As another strategy increasing immunogenicity, the cotreatment of DOX and Mn

highly reinforced innate immunity, synergistically abating the progression of the tumor [12]. Manganese ion sensitizes the binding of double-stranded RNA to cyclic GMP-AMP synthase (cGAS) even at low RNA concentration, allowing cGAS to produce secondary messenger, cyclic-GMP-AMP (cGAMP) activating stimulator of interferon genes (STING) pathway [13]. Amorphous porous manganese phosphate NPs coated with phospholipids was constructed to encapsulate and deliver DOX by relying on enhanced permeation and retention effect [12]. After the internalization into tumors, the NPs rapidly deconstructed the structure of the manganese phosphate nanoparticle at lysosomal pH, thereby releasing DOX and manganese to promote innate immunity [12]. The coadministration of DOX and manganese ion upregulated CD80

CD8

T cells into tumor and produced TNF-α and IL-6, which was attributed to

CD86+DCs and

the activation of cGAS-STING pathway [12]. The in vivo study showed that combinational therapy suppressed tumor progression by infiltrating cytotoxic CD8

T cells into

tumors in the absence of side effects to other organs [12].

Oxaliplatin (OXA), a platinum-based anticancer agent, has been extensively exploited as an ICD inducer due to ER stress-mediated ICD that OXA can be generate, resulting in higher therapeutic effectiveness. As mentioned earlier, due to a lack of inherent tumor targetability, drug delivery systems are often engineered to safely deliver the therapeutic at the target site. In the case of OXA drug delivery system, OXA-loaded PEG-PLGA NPs effectively induced immunogenic cell death in pancreatic cancer cells compared to other anticancer agents, gemcitabine [14]. NP-mediated OXA delivery highly promoted CRT translocation on pancreatic cancer cells, and increase the extracellular level of ATP and HMGB1, rendering costimulatory markers, CD80 and CD83 upregulated, and also secreting IFN-γ [14]. In vivo, the mice immunized with OXAloaded NP-treated pancreatic cancer cells predominantly abrogated the progression of tumor compared with naked gemcitabine, gemcitabine-loaded NP, and naked OXA

[14]. In a different study, the codelivery of OXA and indoleamine 2,3-dioxygenase 1

(IDO-1) inhibitor maximized cytotoxic T cell immunity to attenuate tumor proliferation

[15]. High expression of IDO-1 can evade immune recognition and appears to be asso-

ciated with poor prognosis in various tumor types [15]. Therefore, the inhibition of IDO-1 may play a key role in impairing Treg activity [15]. Liposome-based NPs incorporating OXA and aNLG919, IDO-1 inhibitor, enable CRT translocation on the cancer

203Challenges and opportunities of nanotechnology in cancer immunotherapy

cell surface, and release of ATP and HMGB1, thereby activating innate (DC maturation) and adaptive immune responses (CD8

T cells infiltrated into tumor) [15]. Furthermore,

the cotreatment of OXA and aNLG919 significantly reduced the proportion of Tregs in tumors along with increasing TNF-α and IFN-γ, showing higher antitumor immunity

[15]. In a similar approach, the NP-based codelivery of OXA and an autophagy inducer

not only induced apoptotic cell death but also predominantly enhanced immunogenicity against colorectal cancer [16]. The NPs were constructed with OXA-tagged hyaluronic acid and amphiphilic peptide-cholesterol (GTFGFRRRRRRRR peptide sequence) to load an autophagy inducer, STF-62247, and safely deliver the payloads in cancer cells

[16]. After the internalization of NPs, NPs rendered OXA and STF-62247 released in

the cytosol by cleaving the ester bond and TGF peptide sequence, esterase, and autophagy enzyme, respectively [16]. The codelivery accelerated CRT translocation on cancer cell surfaces and also the release of HMGB1 and ATP, thereby activating DCs and expanding the population of CD4

CD4+and IFN-γ+CD8+T cells [16].

and CD8+T cells, especially in IFN-

Similar to encapsulating ICD inducers, prodrug approaches have been developed to improve the therapeutic effects while h minimizing cargo release at undesirable sites and times [17]. The general prodrug strategy is that ICD inducers are conjugated to functional moieties of polymers, phospholipids, and inorganic materials with stimuli-cleavable linkers (pH, redox-potential, light, and enzyme) [17]. Using the different environments between normal and tumor environments, the prodrugs can be promptly evacuated from their scaffold via stimuli-responsive cleavage [17]. For example, a polymeric prodrug was prepared by Passerini reaction between cinnamaldehyde, 4-formylbenzeneboronic acid pinacol ester, and 5-isocyanpent-1-yne, followed by click reaction with PEG-poly-

L-

glutamate [17]. The polymeric prodrugs self-assembled into NPs with 40 nm in hydrodynamic radius, and were rapidly deconstructed by responding to pH and reactive oxygen species in the cytoplasm, thereby releasing quinone methide for GSH depletion and cinnamaldehyde for ROS amplification [18]. The infliction of amplified oxidative stress to cancer cells triggered CRT translocation to their surface, and elevated extracellular ATP and HMGB1 concentrations, thus upregulating CD80 expression [18]. The treatment of the polymeric prodrug in vivo considerably escalated the population of CD4

CD8

T cells, mature DCs, M1 macrophage infiltrated into the tumor while decreasing

and

that of Tregs and M2 macrophages, thereby eradicating the established tumor [18]. Yet as another example using a prodrug approach, the prodrug-based cotreatment of epirubicin and PD-L1-blocking agent not only induced ICD but also enhanced tumor-specific T cell immunity by inhibiting PD-L1 expression on cancer cells [19]. Two different polymers were synthesized; poly-N-hydroxypropylmethacrylamide labeled with epirubicin and PD-L1-binding sequence using an enzymatic cleavable linker [19]. The polymeric prodrug was able to translocate CRT on the surface of cancer cells and emit immunostimulatory molecules, ATP, and HMGB1 by releasing the epirubicin by

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dissociating the cleavable linkers, thus recruiting DCs and elevating the proportion of

CD86

and major histocompatibility class (MHC) II+DCs in tumor-infiltrating cells

[19]. Although APCs stimulated ICD, there was also the expansion of the population

of CD8

T cells infiltrating into the tumor. These Tregs and PD-L1+cancer cells were also elevated, leading to the failure of cancer immunotherapy [19]. In order to efficiently block PD-L1 receptors, the PD-L1-blocking polymers were cotreated and showed a remarkable reduction of PD-L1 expression on cancer compared to the treatment of PD-L1 antibody owing to lysosomal degradation of PD-L1 receptors [19]. The cotreatment of two polymeric prodrugs shifted the tumor microenvironment with a tumor-suppressive mode by augmenting the proportion of tumor-infiltrating CD8

T cells, particularly CD44+CD62LCD8+T cells and IFN-γ+CD8+T cells alongside decreasing that of Tregs and PD-L1

cancer cells [19].

Ferroptosis is iron-dependent programmed cell death induced by iron overloadmediated lipid peroxidation [20]. Recent studies reported that ferroptosis triggered immunogenic cell death and could be harnessed in cancer immunotherapy. In one study, Fe

magnetic NPs coated with PD-1 antibody-tethered leukocyte membranes

3O4

induced ferroptosis-mediated ICD and inhibited TGF-β signaling pathway [21]. The Fe

magnetic NPs were deconstructed to release ferric ions that can catalyze the

3O4

Fenton reaction, thereby exerting oxidative stress on cancer cells [21]. Ferroptosismediated ICD induction and TGF-β inhibition reset tumor microenvironments with tumor-suppressive modes by increasing the ratios of cytotoxic T cells to Tregs, and M1 to M2 macrophages, thereby not only abating tumor growth but also inhibiting the recurrence of tumor [21]. As another strategy of ferroptosis-mediated ICD, enzyme-like NPs with TGF-β inhibitor accelerated macrophage polarization by exerting oxidative stress to macrophages and overcoming hypoxia [22].H

-responsive iron-

2O2

manganese silicate NPs with TGF-β inhibitors induced catalytic reactions by decomposing hydrogen peroxide into hydroxyl radical and oxygen, respectively. The ROS overproduction activated ferroptosis in cancer cells by downregulating the expression of glutathione peroxidase 4 and also supply large amount of oxygen across tumor tissues to quench hypoxia [22]. The dual therapeutic effect by the enzyme-like NPs increased M1/M2, CD4

/Treg, and CD8+/Treg ratios into the tumor, leading to a

remarkable antitumor effect [22].

2.2 Photodynamic therapy-based ICD

Photodynamic therapy (PDT) destroys cancer cells by light-activated ROS generation such as oxygen, hydrogen peroxide, hydroxyl, and superoxide anion radicals [1,23]. PDT strongly impairs subcellular organelles and plasma membranes [1,23]. Also, dying tumor cells emit tumor-associated antigens and immunostimulatory molecules that trigger inflammation and generate tumor-specific immunogenicity [1,7]. PDT-based mod- ulation of tumor microenvironments highly promoted innate immunity, thereby

stimulating adaptive immunity to kill tumors (Fig. 2) [1]. Various NP-based PDTs have been broadly developed to safely deliver PDT agents in tumor cells and also improve the limited potency of immunogenicity (Fig. 2). We discuss the recent development in NP-based PDT strongly inducing immunogenic cell death.

In general, tumor microenvironments create oxygen-depleting conditions that are called “hypoxia,” weakening PDT-mediated ROS generation [24]. Oxygen supply to the hypoxic tumors is an effective approach to overcome the limitation of light-triggered ROS generation [25]. Oxygen-carrying NPs shifted hypoxia to normoxia by increasing oxygen concentration in tumors and also ameliorated the effectiveness of PDT [25].To be exemplified, NPs that can carry oxygen cancers were able to activate both innate and adaptive immunity as well as augment the efficacy of PDT [25]. The oxygen-carrying NPs were formed with human serum albumin, hemoglobin, and chlorine 6 [25]. The NPs allowed for transporting oxygen molecules across tumor microenvironments to address the hypoxia and also efficiently triggered light-triggered ROS overproduction into the tumor, thereby activating CRT translocation and release of HMGB1 and ATP [25]. PDT-mediated DAMPs dysregulated a proportion of MHCII

CD86

DCs, thus abrogating primary and distant tumors by recruiting tumor-infiltrating cytotoxic CD4

and CD8+T cells, and NK cells [25]. As another example, metal-organic framework (MOF)-based NPs was able to carry oxygen molecules into the tumor and provoke PDT-induced immunogenicity against the tumor [26]. Iron-based MOF was constructed from Fe

O cluster and 5,10,15,20-tetra(p-benzoato)porphyrin [26]. When

the laser was irradiated in the tumor site, the MOF-based NPs catalyzed a cascade reaction to generate oxygen molecules via the Fenton reaction. The generated oxygen molecules were converted to reactive singlet oxygen activated by an excited photosensitizer

[26]. The MOF-based PDT treatments released tumor-associated antigens, translocated

CRT on tumor cell surfaces, and also downregulated hypoxia-inducing factor-1α, thus abolishing primary and distant tumors by elevating the population of DCs, macrophages,

CD4

and CD8+T cells along with lowering that of Tregs [26].

ROS production in ER imposes ER stress on cancer cells, thereby inducing effective ICD that allows innate immunity strongly stimulated [7]. Therefore, ER-targeting photosensitizers have been recently devised to tremendously trigger the release of DAMPs

[27]. In one example, NPs incorporating ER-translocating photosensitizer predomi-

nantly induced ER stress-mediated ICD, thus stimulating both innate and adaptive immunity for enhancing cancer immunotherapy [27]. The ER-translocating photosensitizer was constructed by attaching the p-tosyl group to a porphyrin-based analog to target the ER, and loaded into PEG-liposome-based NPs [27]. This photosensitizer upregulated DAMP signals, CRT translocation, and HMGB1 release compared to non-ER targeting photosensitizer. Thus increasing the proportion of CD80

CD86

DCs and secretion of TNF-α and IL-12p40 [27]. Moreover, the successful stimulation of DCs by ER stress-mediated ICD expanded the population of IFN-γ

CD8+T cells

and recruited cytotoxic T cells infiltration into the tumor [27].

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PDT treatment combined with agents capable of modulating tumor microenvironments has been shown to promote robust and systemic antitumor immunity for enhanced cancer immunotherapy [28]. In one example, natural killer (NK) cell membrane-cloaked NPs incorporating photosensitizer not only stimulated the release of DAMPs but also reeducated macrophage phenotype to M1 mode, thereby inhibiting primary and abscopal tumor growth [28]. NK cell-coated NPs were prepared with photosensitizerloaded PEG-PLGA NPs and NK cell membranes to deliver the payload into the tumor and modulate tumor microenvironments by M1 macrophage polarization [28]. The proteins on NK cell membranes are capable of interacting with M2 macrophages to induce proinflammatory macrophage polarization. Moreover, the interaction of the proteins with M2 macrophages was able to activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), thereby upregulating M1 markers, iNOS, CD86, TNFα, IL-6, and IL-12 along with reducing M2 markers, IL-10 and CD206 [28]. When the tumor was irradiated by laser treatment, the photosensitizer wreaked oxidative damage to cancer cells, thus accelerating CRT translocation and release of ATP and HMGB1

[28]. The dual function achieved by NK cell-membrane-coated NPs ultimately drove

enhance innate (activated DCs and M1 macrophages) and adaptive immune responses (cytotoxic CD4

and CD8+T cell infiltrated into tumor) [28].

To sensitize cytotoxic T cell immunity against cancer cells, PDT cotreatment with IDO-1 inhibition was harnessed in cancer immunotherapy by suppressing Treg activity

[29]. For instance, the codelivery of photosensitizer and IDO-1 inhibitor allowed for

both ICD induction and Tregs suppression to improve the therapeutic effectiveness

[29]. The NP was constructed with PEG-pH-responsive polypeptides and photosensi-

tizer and IDO-1 inhibitor to safely deliver the payload into the tumor [29]. The IDO inhibitor, indoximod, abolished the mammalian target of the rapamycin (mTOR) pathway and also interference with S6K phosphorylation. Inhibiting the pathway diminished Treg activity while laser-irradiated photosensitizer induced ER stress-medicated ICD bringing about CRT translocation and release of ATP and HMGB1 [29]. The PDTbased cotreatment significantly escalated the tumor-infiltrating cytotoxic CD8

T cells alongside decreasing the portion of Tregs in the lesion, which could repress primary and distant tumors by establishing robust antitumor immunity [29]. In a complementary study, the dual-responsive prodrug NP system strengthened antitumor T cell immune responses with selective activation of therapeutic effects in colorectal cancer

[30]. PEG was appended to a photosensitizer with a matrix metalloproteinase-2

(MMP-2)-cleavable linker while NLG919, an IDO inhibitor, was tagged to phospholipid with a disulfide-bond to self-assemble into an NP [30]. The tumor microenvironments allowed the structure of NPs to rapidly collapse by dissociating both the MMP and disulfide linkers, thus releasing the photosensitizer and NLG919 [30]. Likewise, NLG919 upregulated antitumor immunity by decreasing the portion of Tregs while DAMPs were emitted promptly via laser irradiation, promoting DC maturation and antigen

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