Immunogenic Death Research Articles

Evoking tumor associated macrophages by mitochondria-targeted magnetothermal immunogenic cell death for cancer immunotherapy

Immunogenic cell death (ICD) based on endoplasmic reticulum (ER) stress has been widely studied as the fundamentals of cancer immunotherapy. However, the currently available ICD inducers are still very rare and mostly highly toxic chemotherapeutic drugs. Herein, a novel ICD modality based on mitochondrial heat stress by magnetic hyperthermia treatment (MHT), is proposed for effectively evoking tumor-associated macrophages (TAMs) against cancer cells. A monodisperse and biocompatible nanomedicine by grafting arginyl-glycyl-aspartic acid (RGD) and (3-carboxypropyl)triphenylphosphonium bromide (TPP) onto the surface of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles (MNPs), named as MNPs-RGD-TPP (MRT), was synthesized for mitochondrial heat stress-induced oxidative damage of tumor cells under the magnetothermal manipulation. Such heat stress-damaged mitochondria can cause the immunogenic death of tumor cells to release damage-associated molecular patterns (DAMPs), including ATP and HSP 70, to M1-polarize TAMs, resulting in the reactivated immunoresponse of macrophages against cancer cells. The effectiveness and robustness of MRT nanomedicine in evoking TAMs-mediated extracellular killing or phagocytosis are verified both in vitro and in vivo. Such a therapeutic approach based on mitochondria-targeted magnetothermal ICD for activating TAMs may be instructive to future anticancer immunotherapy.

A heterogenic membrane-based biomimetic hybrid nanoplatform for combining radiotherapy and immunotherapy against breast cancer

Radiotherapy is adopted to obliterate multiple malignant tumors clinically, which might also induce antitumor immune response. However, traditional radiotherapy is not enough to ablate tumors and activate long-term immunological response. Here, we developed a hybrid nanoplatform (MGTe) composed of GTe (glutathione (GSH) decorated Te nanoparticles) and fusing tumor cell membranes (TM) and bacterial outer membranes (BM). In this nanoplatform, GTe was designed for radiotherapy sensitization, concurrently the fusion of TM and BM was expected for amplifying antitumor immune. With a high-Z element, MGTe could enhance radiosensitivity by reactive oxygen species (ROS) production and cancer cell immunogenic death (ICD) under X-ray irradiation, which would also trigger antitumor immune. At meanwhile, TM and BM would further enlarge the immunological effects through antigen presenting cells (APCs) maturation and cytotoxic T lymphocytes (CTLs) stimulation. In this synergistic strategy, the combination of MGTe and X-ray showed significant tumor inhibition by radiation-driven immunotherapy, which will find great potential as an attractive clinical alternative to fight against tumor with reduced side effects.

Hydrazide-manganese coordinated multifunctional nanoplatform for potentiating immunotherapy in hepatocellular carcinoma

Immune checkpoint blockade (ICB)-based immunotherapy is a revolutionary therapeutic strategy for hepatocellular carcinoma (HCC). However, tumor immune tolerance and escape severely restrict the therapeutic efficacy of ICB therapy. It is urgent to explore new strategies to potentiate ICB therapy in HCC. Herein, we developed manganese oxide-crosslinked bovine albumin/hyaluronic acid nanoparticles (BHM) by an innovative hydrazide-manganese coordination and desolvation process. Successive loading of doxorubicin (DOX) and indocyanine green (ICG) was achieved via hydrazone linkage and electrostatic interactions, respectively, obtaining DOX/ICG-coloaded BHM nanoplatform (abbreviated as BHMDI). The BHMDI nanoplatform exhibited a high drug content (>46%) and pH/reduction dual-responsive drug release behavior. The nanoplatform could efficiently alleviate tumor hypoxia by catalytic decomposition of intracellular H2O2 to O2 and significantly improve BHMDI-based photodynamic chemotherapy efficacy. The BHMDI nanoplatform downregulated the proportion of alternatively activated (M2) macrophages in tumors and simultaneously induced immunogenic death of HCC cells, thus promoting the maturation of dendritic cells and ensuing priming of CD4+ and CD8+ T cells. Importantly, programmed death-1 (PD-1) blockade in combination with BHMDI nanoplatform not only eradicated primary tumors but inhibited tumor recurrence, abscopal tumor growth and lung metastasis of HCC by triggering robust systemic antitumor immunity. This work proved the feasibility of BHMDI-based photodynamic chemotherapy for potentiating PD-1 blockade immunotherapy by reversing hypoxic and immunosuppressive tumor microenvironment.

Constructing a nanocage-based universal carrier for delivering TLR-activating nucleic acids to enhance antitumor immunotherapy

Toll-like receptors (TLRs) have recently emerged as one of the potential targets for immune activation. Therefore, TLR agonists have gotten much attention in the immunotherapy field, and have been proven effective in activating antigen-presenting cells (e.g., dendritic cells) and extensively studied for immune adjuvants. However, the applications of TLR-activating nucleic acids are severely limited by their poor effectiveness and utilization in vivo. Herein, we rationally bioengineered the natural nanocage-like protein, human heavy chain ferritin (HFn), with a positively charged cavity to construct a series of HFn(+) mutants for the internal encapsulation of TLR-activating nucleic acids via electrostatic interaction. Through systematic screenings, we selected the optimal HFn(+) nanocarrier and identified its universal loading ability for different types of TLR-activating nucleic acids. Through in vitro and in vivo experiments, we found that HFn(+) nanocarrier has significantly improved the delivery efficiency of TLR-activating nucleic acids, achieving efficient cell uptake, specific lysosomal localization and enhanced immune activation. Moreover, by virtue of its cage-like spatial structure, TLR-activating nucleic acid loaded HFn(+) shows great potential in combination with the other existing immune strategies via externally modifying function modules. In this study, we conjugated photodynamic photosensitizer chlorin e6 (Ce6) on the external surface of the HFn(+) carrier as an immunogenic death (ICD) inducer. The results show that the HFn(+)-based all-in-one platform effectively synergized TLR agonist-mediated and ICD-mediated immune activation, as evidenced by inducing significantly systemic immune responses, antitumor abscopal effect, and anti-metastasis efficacy in vivo. In conclusion, this nanocage-based carrier is a convenient and universal vehicle to effectively deliver different TLR-activating nucleic acids in vivo and may serve as a novel strategy for the combination of antitumor immunotherapies.

Lentinan Enhances the Function of Oxaliplatin on the Esophageal Tumors by Persuading Immunogenic Cell Death.

Objective The focus of this research was to look at the effects of the combination of the lentinan (LNT) and oxaliplatin (Oxa) on the apoptosis of human esophageal cancer cells, as well as the underlying mechanism. Methods LNT and Oxa were used to treat EC-109 human esophageal cancerous cells at various doses, and the cell survival rate was measured using the Cell Counting Kit-8 (CCK-8) assay. In addition, 24 h after treatment of EC-109 cells with a combination of LNT and Oxa, flow cytometry was used to analyze their apoptotic effect on these cells. Additionally, LNT on EC-109 cell apoptotic upshot was assessed via measuring the consequence of LNT on the mRNA and protein expression levels pertaining to immunogenic cell death factors CALR, HSP90, and HSP70 by qPCR (quantitative real-time polymerase chain reaction) and western blot analysis, correspondingly. Results Cell proliferation was inhibited only when EC-109 cells were added with LNT at 1,200 μg/mL to the maximum concentrations, but the combination of LNT and Oxa at a low dose (800 μg/mL and 20 μM, respectively) significantly increased their sensitivity to Oxa and reduced their proliferation (P < 0.05), and their apoptosis was significantly increased by LNT (P < 0.05). The immunogenic cell death-related genes CALR, HSP90, and HSP70 had dramatically enhanced mRNA and protein expression levels after therapy with a combination of LNT and Oxa (P < 0.05). Conclusion These data imply that LNT increases the susceptibility of esophageal cancerous cells to Oxa by driving EC-109 cells to display immunogenic death. Therefore, LNT combined with Oxa may be an effective method in esophageal cancer management.

Optimization of whole-cell vaccines with CpG/αOX40/cGAMP to strengthen the anti-tumor response of CD4+ T cells in melanomas

MethodsIn this study, we developed a strategy for the prevention and therapy of melanoma using a whole-cell vaccine combined with a CpG/αOX40/cGAMP triple adjuvant. The CpG/αOX40/cGAMP triple adjuvant was used to co-culture melanoma cells in vitro to induce immunogenic death of tumor cells. The mixture of inactivated tumor cells and the triple drug was an optimized tumor whole-cell vaccine, which was injected subcutaneously into mice for tumor prevention and therapy. Furthermore, we analyzed the changes of immune cells in spleen and tumor by flow cytometry and immunohistochemistry, and detected the changes of cytokines after vaccine application by cytometric bead array to explore the specific mechanism of vaccine.ResultsIn vaccine prevention and therapy experiments, it was observed that the tumor growth was significantly inhibited in the whole-cell vaccine group, and the survival time of mice was significantly prolonged. Flow cytometry results showed that the proportion of CD4+ T cells and CD8+ T cells in tumor of mice in vaccine group was higher than that in control group, especially the CD4+ T cells.ConclusionThe optimized vaccine has the unique ability to amplify tumor-specific CD4+ T cells, which improves antitumor sensitivity, and has a significant effect on the prevention and therapy of melanoma mice.

Abstract 6216: Intratumoral B0112 in combination with radiotherapy synergizes to achieve CD8 T cell mediated local tumor control

Abstract Background: Radioimmunotherapy combines irradiation of tumor lesions with immunotherapy to achieve local and abscopal control of cancer. Most immunotherapy agents are given systemically, but strategies for delivering immunotherapy locally are under clinical scrutiny to maximize efficacy and avoid toxicity. Local immunotherapy by injecting various patterns of molecules shows efficacy both preclinical and clinically. BO112 is a viral mimetic based on nanoplexed double stranded RNA (poly IC) which exerts immune-mediated antitumor effects in mice and humans upon intratumoral delivery. BO112 and external beam irradiation were used to make the proof-of-concept local immunotherapy plus radiation therapy combinations. Methods: Murine transplantable tumor cells lines (TSA, MC38 and B16 ova) were used to show increased immunogenic features under irradiation as well as bilateral tumor models in which only one of the lesions could be irradiated. Flow cytometry on cell suspensions from tumor draining lymph nodes and multiplex tissue immunofluorescence were used to determine mechanims of antitumor immunity. Depletions of immune cell populations and knock out mice for IFNAAR and BAFT3 genes were used to delineate the immune system requirements for efficacy. Results: In cultures of TSA breast cancer cells the combination of irradiation and BO112 showed more prominent features of immunogenic tumor-cell death including type I interferon reléase. Injection of BO112 in the tumor lesions under radiation achieved excellent control of the treated tumors whilst modest delays in contralateral tumor progression were observed. Local effects were associated with more prominent presence of antitumor CTLs and cDC1 dendritic cells in the tumor and regional lymph nodes. Importantly, local irradiation plus BO112 in a tumor lesion enhanced the therapeutic effect of radiotherapy on distant uninjected tumor lesion. Conclusions: This study demonstrates that local BO112 immunotherapy and external beam radiation therapy can exert synergies to achieve local tumor control. This beneficial effect can be extended to non-injected lesions as long as they are also irradiated, suggesting strategies to treat oligometastatic patients with lesions susceptible to radiotherapy and at least one of them accessible for BO112 repeated intratumoral injections. Citation Format: Maria.E. Rodriguez-Ruiz, Irantzu serrano, Eneko Garate, Inmaculada Rodriguez, maite alvarez, Carmen Molina, Miguel Fernandez de Sanmamed, Leire Arbea, Marta Moreno, Marisol Quintero, Ignacio Melero. Intratumoral B0112 in combination with radiotherapy synergizes to achieve CD8 T cell mediated local tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6216.

Immune response induced by hematoporphyrin derivatives mediated photodynamic therapy: Immunogenic cell death and elevated costimulatory molecules

Photodynamic therapy (PDT) not only destroys tumor cells directly but also induced anti-tumor immune response through damage-associated molecular patterns (DAMPs). It is reported that anti-tumor response was associated with light dose and photosensitizer used in PDT. In this study, 4T1 tumor cells were implanted on both the right and left flanks of mice. Only the right tumor was treated by HpD-PDT, while the left tumor was not irradiated. The anti-tumor immune response induced by HpD-PDT was investigated. The expression of DAMPs and co-stimulatory molecules induced by HpD-PDT were tested by immunofluorescence and flow cytometry in vivo. Different light doses of PDT were designed to treat 4T1 cells. The killing effect was assessed by CCK-8 kit and apoptosis kit. The expression of DAMPs on 4T1 cells after HpD-PDT were evaluated by flow cytometry, western blot and ATP kit. This study showed that CD4[Formula: see text]T, CD8[Formula: see text]T and the production of IFN-[Formula: see text] were increased significantly on day 10 in right-tumor after PDT treatment compared with control group. HpD-PDT enhanced the expression of calreticulin (CRT) on tumor tissue. Importantly, co-stimulatory molecular OX-40 and 4-1BB were elevated on CD8[Formula: see text]T cells. In vitro, immunogenic death of 4T1 cells was induced after PDT. Besides, the expression of DAMPs increased with the increasing of energy density. This study indicates that anti-tumor immune effect was induced by HpD-PDT. The knowledge of the involvement of CRT, ATP and co-stimulatory molecules uncovers important mechanistic insight into the anti-tumor immunogenicity. It was the first time that co-stimulatory molecules were investigated and found to elevate after PDT.

Camrelizumab in combination with fluorouracil or taxol plus platinum chemotherapy as first-line treatment of esophageal squamous cell carcinoma: A multicenter, open-label, prospective cohort study.

e16084 Background: The introduction of immune checkpoint inhibitors (ICIs) after chemotherapy and targeted therapy has altered the treatment pattern of esophageal squamous cell carcinoma (ESCC). However, using ICIs alone results in a poor response rate. Fortunately, fundamental research indicates that chemotherapy might trigger immunogenic death of tumor cells by releasing tumor antigens, hence eliminating immune system repression of tumor cells. On this basis, a number of clinical studies, including KEYNOTE-590, CheckmMate-648, ORIENT-15, and ESCORT-1st, on the first-line treatment of ESCC with ICIs coupled with chemotherapy, including fluorouracil or taxol and platinum (PF or TP), were conducted and yielded favorable results. However, the advantage of safety and effectiveness of ICIs combination with PF and TP in Chinese ESCC remains unknown. Furthermore, since the southeast part of Shanxi province has a high prevalence of esophageal cancer, the geographical features of ESCC patients will be examined. Methods: Camrelizumab was maintained after 6 cycles of camrelizumab in combination with PF or TP chemotherapy. From May 2020 to February 2022, our study has included 40 locally progressed and advanced ESCC patients. Camrelizumab was administered in combination with PF to 11 patients and TP to 29 patients. Every 6 weeks, efficacy was examined using RECIST 1.1, and 33 patients were evaluated. This research was registered with the Chinese Clinical Trials Registry (ChiCTR2000037942). Results: The median treatment time was 5.8m. 82.5% (33/40) patients were availably evaluated. The objective response rate (ORR) was 72.7% (24/33) and the disease control rate (DCR) was 97.0% (32/33). There is no statistically significant difference in ORR ( p=0.1779) and DCR ( p=0.1005) between PF and TP (55.6% vs 79.2%, 88.9% vs 100%) regimens. At this moment, mPFS has not been achieved. The most common adverse events (AEs) were anemia (22.5%, 9/40), lymphocytopenia (15%, 6/40), neutropenia(15%, 6/40), reactive cutaneous capillary endothelial proliferation (RCCEP) (12.5%, 5/40) and fatigue (7.5%, 3/40). Thrombocytopenia (2.5%, 1/40), neutropenia (2.5%, 1/40) and leukopenia (2.5%, 1/40) were the most common grade 3 or 4 toxicities The most frequently reported immune-related AEs were RCCEP (12.5%, 5/40) and hypothyroidism (7.5%, 3/40). There were no new significant adverse events. Conclusions: Camrelizumab in combination with chemotherapy is a promising regimen with good tolerability in the first-line treatment of ESCC. Compared with FP, TP had more therapeutic advantages, But the result is a stage summary, and further observation is needed. Clinical trial information: ChiCTR2000037942. [Table: see text]

NIR-II Responsive Molybdenum Dioxide Nanosystem Manipulating Cellular Immunogenicity for Enhanced Tumor Photoimmunotherapy.

Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has emerged as a better candidate for deep-tissue tumor elimination. More interestingly, the photothermal ablated tumor cells also manifest somewhat immunostimulation potency to elicit antitumor immunity, although most dying cells are undergoing apoptosis that is commonly considered as immunologically silent. Here, a NIR-II responsive nanosystem is established for tumor photoimmunotherapy using molybdenum dioxide (MoO2) nanodumbbells as the nanoconverter. Meanwhile, an apoptosis-blocking strategy is proposed to regulate the cell death pattern under NIR-II laser irradiation in order to improve the immunogenic cell death. The nanoformulation can efficiently block caspase 8-dependent apoptotic pathway in photothermal ablated tumor cells and transform into more immunogenic death patterns, thereby activating systemic immunity to inhibit tumor growth and metastasis. In addition, this strategy also helps enhance the body's responses to α-PD-1 immune checkpoint inhibitor, which implies a potential optimal combination for cancer immunotherapy.

A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates tumors and induces antitumor immunity

Despite recent advances in cancer therapy, hard-to-reach, unidentified tumors remain a significant clinical challenge. A promising approach is to treat locatable and accessible tumors locally and stimulate antitumor immunity in situ to exert systemic effects against distant tumors. We hypothesize that a carrier of immunotherapeutics can play a critical role in activating antitumor immunity as an immunoadjuvant and a local retainer of drug combinations. Here, we develop a polyethyleneimine-lithocholic acid conjugate (2E′), which forms a hydrophobic core and cationic surface to codeliver hydrophobic small molecules and anionic nucleic acids and activates antigen-presenting cells via the intrinsic activities of 2E′ components. 2E′ delivers paclitaxel and small-interfering RNA (siRNA) targeting PD-L1 (or cyclic dinucleotide, [CDN]) to induce the immunogenic death of tumor cells and maintain the immunoactive tumor microenvironment, and further activates dendritic cells and macrophages, leveraging the activities of loaded drugs. A single local administration of 2E′ or its combination with paclitaxel and PD-L1–targeting siRNA or CDN induces strong antitumor immunity, resulting in immediate regression of large established tumors, tumor-free survival, an abscopal effect on distant tumors, and resistance to rechallenge and metastasis in multiple models of murine tumors, including CT26 colon carcinoma, B16F10 melanoma, and 4T1 breast cancer. This study supports the finding that local administration of immunotherapeutics, when accompanied by the rationally designed carrier, can effectively protect the host from distant and recurrent diseases.

Framework Nucleic Acid Immune Adjuvant for Transdermal Delivery Based Chemo-immunotherapy for Malignant Melanoma Treatment.

Despite the tremendous progresses of cancer immunotherapy, its current clinical responses rate in melanoma remains to be improved. Here, we have reported a skin penetrating tetrahedral framework nucleic acid immune adjuvant (FNAIA) to transdermally deliver chemotherapy drugs into melanoma to induce the immunogenic death of tumor cells and expose tumor antigens, which with assistance of CpG oligodeoxynucleotide incorporated in FNAIA could trigger systemic tumor-specific immune responses. Compared with free CpG, FNAIA could penetrate deeper into subcutaneous tumor tissues and more effectively stimulate dendritic cell maturation. Notably, doxorubicin-loaded FNAIA locally applied on the intact skin above the melanoma could effectively inhibit the growth of mouse B16F10 melanoma and increase tumor CD8+ T cell infiltration. Moreover, combined with immune checkpoint inhibitor, the growth of distant tumors could also be effectively inhibited, suggesting that this strategy could induce systemic immune responses. Therefore, this work provides a new idea for non-invasive treatment of skin cancer.

Gold Glyconanoparticles Combined with 91–99 Peptide of the Bacterial Toxin, Listeriolysin O, Are Efficient Immunotherapies in Experimental Bladder Tumors

Simple SummaryWe propose a novel type of immunotherapy for bladder cancer using gold nanoparticles bound to a peptide of a bacterial toxin with anti-tumor capacities as listeriolysin O called Listeria nanovaccines. Here, we present the pre-clinical experiments on a mice model of bladder cancer and blood cells of patients with bladder cancer using these Listeria nanovaccines that activate the immune system, block the tumor immunosuppression environment, and reduce the tumor size. The impact of Listeria nanovaccines on the field of immunotherapies for solid tumors can be extended to other solid tumors containing lymphocyte infiltration. Therefore, we propose Listeria nanovaccines as immunotherapy for tumors such as melanoma, urothelial bladder carcinoma, non-small cell lung carcinoma, and glioblastoma.This study presents proof of concept assays to validate gold nanoparticles loaded with the bacterial peptide 91–99 of the listeriolysin O toxin (GNP-LLO91–99 nanovaccines) as immunotherapy for bladder tumors. GNP-LLO91–99 nanovaccines showed adjuvant abilities as they induce maturation and activation of monocyte-derived dendritic cells (MoDCs) to functional antigen-presenting cells in healthy donors and patients with melanoma or bladder cancer (BC), promoting a Th1 cytokine pattern. GNP-LLO91–99 nanovaccines were also efficient dendritic cell inducers of immunogenic tumor death using different bladder and melanoma tumor cell lines. The establishment of a pre-clinical mice model of subcutaneous BC confirmed that a single dose of GNP-LLO91–99 nanovaccines reduced tumor burden 4.7-fold and stimulated systemic Th1-type immune responses. Proof of concept assays validated GNP-LLO91–99 nanovaccines as immunotherapy by comparison to anti-CTLA-4 or anti-PD-1 antibodies. In fact, GNP-LLO91–99 nanovaccines increased percentages of CD4+ and CD8+ T cells, B cells, and functional antigen-presenting DCs in tumor-infiltrated lymphocytes, while they reduced the levels of myeloid-derived suppressor cells (MDSC) and suppressor T cells (Treg). We conclude that GNP-LLO91–99 nanovaccines can work as monotherapies or combinatory immunotherapies with anti-CTLA-4 or anti-PD-1 antibodies for solid tumors with high T cell infiltration, such as bladder cancer or melanoma.

Therapeutic Effects of Cold Atmospheric Plasma on Solid Tumor.

Cancer is a devastating disease, and there is no particularly effective treatment at present. Recently, a new treatment, cold atmospheric plasma (CAP), has been proposed. At present, CAP is confirmed to have selective killing effect on tumor by many studies in vitro and in vivo. A targeted literature search was carried out on the study of cold atmospheric plasma. Through analysis and screening, a narrative review approach was selected to describe therapeutic effects of cold atmospheric plasma on solid tumor. According to the recent studies on plasma, some hypothetical therapeutic schemes of CAP are proposed in this paper. The killing mechanism of CAP on solid tumor is expounded in terms of the selectivity of CAP to tumor, the effects of CAP on cells, tumor microenvironment (TME) and immune system. CAP has many effects on solid tumors, and these effects are dose-dependent. The effects of optimal doses of CAP on solid tumors include killing tumor cells, inhibiting non-malignant cells and ECM in TME, affecting the communication between tumor cells, and inducing immunogenic death of tumor cells. In addition, several promising research directions of CAP are proposed in this review, which provide guidance for future research.

PD-L1 blockade potentiates the antitumor effects of ALA-PDT and optimizes the tumor microenvironment in cutaneous squamous cell carcinoma

ABSTRACT Immune checkpoint blockade (ICB) is a powerful oncologic treatment modality for a wide variety of human malignancies, but the patient response rate to this treatment remains low, especially in patients with cutaneous squamous cell carcinoma (cSCC). 5-Aminoleuvulinic acid-photodynamic therapy (ALA-PDT) is widely used to treat cancerous and precancerous skin diseases, but the value of ALA-PDT in the treatment of invasive cSCC is debatable. Our previous studies have shown that ALA-PDT can induce antitumor immune responses by promoting the immunogenic death of tumor cells. However, it is unclear whether ALA-PDT exerts synergistic effects with ICB in cSCC. Here, we report that PD-L1 blockade potentiates the antitumor effects of ALA-PDT both on primary and distant tumors, and optimizes the tumor microenvironment in cSCC. In this study, we first detected PD-L1 expression in patients with different grades of cSCC. Then we found the combination of anti-PD-L1 monoclonal antibody (mAb) and ALA-PDT killed tumor cells by apoptosis- and/or ferroptosis-mediated immunogenic cell death (ICD) and stimulated systemic immune response, as well as building the immunological memory response to prevent tumor recurrence. Furthermore, we found that combination therapy can be used to recruit tertiary lymphoid structure (TLS)-like intratumoral lymphoid aggregates, which may promote tumor-infiltrating lymphocyte (TIL)-mediated antitumor immunity. In summary, our work demonstrates that ICB treatment with an anti-PD-L1 antibody is a promising strategy that may potentiate the antitumor effects of ALA-PDT in cSCC.

Tumor-derived exosomes co-delivering aggregation-induced emission luminogens and proton pump inhibitors for tumor glutamine starvation therapy and enhanced type-I photodynamic therapy

Although promising, the efficiency of aggregation-induced emission luminogens (AIEgens)-based photodynamic therapy (PDT) is limited by cellular glutathione (GSH). GSH is not a terminal reducing agent but it can be oxidized and subsequently reduced to its original state by reductases to further participate in antioxidant activity. It is therefore imperative to control GSH for effectively inducing oxidation within tumor cells. Recent studies showed that tumor cell metabolism depends mainly on glutamine, which is also the nitrogen and ATP source for GSH synthesis. Therefore, glutamine-based starvation therapy may be effective in enhancing photodynamic therapy. In this work, tumor-derived exosomes were developed for co-delivering AIEgens and proton pump inhibitors (PPI) for tumor combination therapy. Tumor-derived exosomes could specifically deliver drugs to the tumor sites, where PPI inhibited cell glutamine metabolism, suppressed tumor cell GSH and ATP production, and improved the effect of type-I PDT from AIEgens. When used in the treatment of MGC803 gastric cancer subcutaneous model, our system shows a high tumor growth inhibition rate, and even promoting tumor immunogenic death. This is the first work which combine inhibition of glutamine metabolism with PDT, and it has the potential to be applied for future designs of new tumor metabolic therapies and photodynamic systems.

Ferroptosis‐Enhanced Cancer Immunity by a Ferrocene‐Appended Iridium(III) Diphosphine Complex

AbstractFerroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis‐inducing agents have great potential as new antitumor candidates. Here, we report a IrIII complex (Ir1) containing a ferrocene‐modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton‐like reaction, produce hydroxyl radicals, induce lipid peroxidation, down‐regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis‐inducing capabilities for effective cancer immunotherapy.

Ferroptosis-Enhanced Cancer Immunity by a Ferrocene-Appended Iridium(III) Diphosphine Complex.

Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis-inducing agents have great potential as new antitumor candidates. Here, we report a IrIII complex (Ir1) containing a ferrocene-modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton-like reaction, produce hydroxyl radicals, induce lipid peroxidation, down-regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis-inducing capabilities for effective cancer immunotherapy.

Glutamine Metabolism-Regulated Nanoparticles to Enhance Chemoimmunotherapy by Increasing Antigen Presentation Efficiency.

Although the strategies to induce dendritic cells (DCs) maturation and promote their antigen presentation can stimulate the tumor immune response, the endogenous deficiency and immunosuppression of DCs reduce antigen utilization, which limits antigen presentation efficiency and reduces immunotherapy effectiveness. Here, we report an endogenous stimulus-responsive nanodelivery system (DOX@HFn-MSO@PGZL). On the one hand, doxorubicin (DOX) promoted antigen presentation by DCs after the immunogenic death of tumor cells. On the other hand, l-methionine sulfoximine (MSO) regulated the glutamine metabolism of tumor-associated macrophages (TAMs) to induce a shift toward the M1-type. M1-TAMs synergistically presented antigens with mature DCs and were more frequently produced to destroy the tumor suppressive immune microenvironment, resulting in the alleviation of DCs functional inhibition. Ultimately, the antigen presentation efficiency was improved, completely activating tumor immunity and exhibiting powerful antitumor effects.

H2O2 Self‐Producing Single‐Atom Nanozyme Hydrogels as Light‐Controlled Oxidative Stress Amplifier for Enhanced Synergistic Therapy by Transforming “Cold” Tumors

AbstractSingle‐atom nanozyme (SAzyme) with peroxidase‐like activity can alter cellular redox balance and shows promising potential for tumor therapy. However, the “cold” immune microenvironment and limited amount of hydrogen peroxide (H2O2) in solid tumors severely restrict its efficacy. Herein, a light‐controlled oxidative stress amplifier system is designed by co‐encapsulating Pd‐C SAzymes and camptothecin in agarose hydrogel, which exhibits enhanced synergistic antitumor activity by self‐producing H2O2 and transforming “cold” tumors. In this nanozyme hydrogel system, the Pd‐C SAzyme converts near‐infrared laser into heat, resulting in agarose degradation and consequent camptothecin release. The camptothecin increases H2O2 level in tumors by activating nicotinamide adenine dinucleotide phosphate oxidase, improving the catalytic performance of SAzymes with peroxidase‐like activity. Moreover, the combination of photothermal therapy, chemotherapy, and nanozyme‐based catalytic therapy further facilitates tumor immunogenic death and enhanced antitumor immunity. The results reveal the synergistic antitumor potential of the novel SAzyme/chemotherapeutics‐based hydrogel system.