Immunogenic Cell Death Research Articles

Dual-Activatable Nano-Immunomodulator for NIR-II Fluorescence Imaging-Guided Precision Cancer Photodynamic Immunotherapy.

Photodynamic immunotherapy which combines photodynamic therapy with immunotherapy has become an important and effective method for the treatment of cancer. However, most cancer photodynamic immunotherapeutic systems are not able to achieve precise release of immunomodulators, resulting in systemic side effects and poor patient outcomes. Herein, a dual-activatable nano-immunomodulator (DIR NP), which both its photodynamic effect and agonist release can be activated under specific stimuli, is reported for precision cancer photodynamic immunotherapy. The DIR NP is self-assembled from an R848-conjugated amphiphilic polymer (mPEG-TK-R848) and a hydrophobic oxidized bovine serum albumin (BSA-SOH)-conjugatable photosensitizer (DIR). DIR NPs may generate a small amount of 1O2 under 808nm laser irradiation, leading to the cleavage of thioketal (TK) moiety and release of R848 and DIR. The released DIR may conjugate with tumor-overexpressed BSA-SOH, improving its photodynamic efficiency and NIR-II fluorescence signal. Such photodynamic efficiency improvement may further enhance the release of cargoes upon irradiation. The activated photodynamic effect induces immunogenic cell death (ICD) to release immune factors and R848 can enhance the maturation of dendritic cells for inhibiting the growth of both primary and distant tumors and eliminating lung metastasis. Therefore, this study provides a dual-activatable intelligent nano-immunomodulator for precise regulation of tumor photodynamic immunotherapy.

NADPH Oxidases-Inspired Reactive Oxygen Biocatalysts with Electron-Rich Pt Sites to Potently Amplify Immune Checkpoint Blockade Therapy.

Clinical immune checkpoint blockade (ICB)-based immunotherapy of malignant tumors only elicits durable responses in a minority of patients, primarily due to the highly immunosuppressive tumor microenvironment. Although inducing immunogenic cell death (ICD) through reactive oxygen biocatalyst represents an attractive therapeutic strategy to amplify ICB, currently reported biocatalysts encounter insurmountable challenges in achieving high ROS-generating activity to induce potent ICD. Here, inspired by the natural catalytic characteristics of NADPH oxidases, the design of efficient, robust, and electron-rich Pt-based redox centers on the non-stoichiometric W18O49 substrates (Pt─WOx) to serve as bioinspired reactive oxygen biocatalysts to potently activate the ICD, which eventually enhance cancer immune responses and amplifies the ICB-based immunotherapy is reported. These studies demonstrate that the Pt─WOx exhibits rapid electron transfer capability and can promote the formation of electron-rich and low oxophilic Pt redox centers for superior reactive oxygen biocatalysis, which enables the Pt─WOx-based inducers to trigger endoplasmic reticulum stress directly and stimulate immune responses potently for amplifying the anti-PD-L1-based ICB therapy. This bioinspired design provides a straightforward strategy to engineer efficient, robust, and electron-rich reactive oxygen biocatalysts and also opens up a new avenue to create efficient ICD inducers for primary/metastatic tumor treatments.

Two‐Step Targeting‐Tunable Semiconducting Nanoswitches Amplify Mitochondrion Damage and PD‐L1 Blockade for Orthotopic Pancreatic Cancer Therapy

AbstractPancreatic cancer is a malignancy tumor with luxuriant extracellular matrix (ECM) and highly immunosuppressive microenvironment and its therapy remains an enormous challenge. A two‐step targeting‐tunable strategy is proposed for orthotopic pancreatic cancer therapy via designing semiconducting nanoswitches (C/SPNT/αP) to amplify the mitochondrion damage and programmed death ligand 1 (PD‐L1) blockade. A mitochondrion‐targeting small nanoparticle (SPNT) consisting of mitochondrial targeting moiety triphenylphosphine (TPP) and semiconducting polymer is embedded with PD‐L1 antibody (αPD‐L1) into sono‐responsive collagen binding peptide (CBP)‐conjugated nanoliposomes to form C/SPNT/αP. In the first targeting step, C/SPNT/αP achieve ECM targeting to observably increase their enrichment into orthotopic pancreatic tumor sites because CBP can effectively bind to collagen in ECM. Upon ultrasound (US) irradiation, C/SPNT/αP mediate a sono‐responsive structural failure via sonodynamic effect for on‐demand releases of SPNT and αPD‐L1. In the second targeting step, SPNT target to mitochondria to induce mitochondrial damage under US irradiation for triggering amplified cell apoptosis and immunogenic cell death (ICD). Moreover, the released αPD‐L1 blocks the immunosuppressive pathway to further boost immunological effect. Such a novel therapeutic regimen can almost completely eradicate orthotopic pancreatic Panc02 and KPC tumors in mouse models. This study presents the first two‐step targeting‐tunable nanomedicine for treatments of deep‐seated orthotopic tumors.

Generating Immunological Memory Against Cancer by Camouflaging Gold-Based Photothermal Nanoparticles in NIR-II Biowindow for Mimicking T-Cells.

Photothermal therapy (PTT) against cancer not only directly ablates tumors but also induces tumor immunogenic cell death (ICD). However, the antitumor immune response elicited by ICD is insufficient to prevent relapse and metastasis because of the immunosuppressive tumor microenvironment (TME). A biomimetic nanoplatform (bmNP) mimicking cytotoxic lymphocytes (CTLs) for combinational photothermal-immunotherapy to effectively regulate the immunosuppressive TME is reported here. The bmNP is constructed by wrapping the T-cell membrane onto a new type of photothermal agents, spherical Au-based PNCs (sAuPNCs). Similar to T-cells, the bmNP enhanced accumulation at the tumor site by targeting the tumor via adhesion proteins on T-cell membrane. The obtained sAuPNCs have a wide absorption band in the second near-infrared (NIR-II) region with a high photothermal conversion efficiency (PCE) up to about 75% and excellent photostability. The bmNP with a smaller size is more superior compete with T-cells to bond with tumor cells via PD-1/PD-L1 interaction to effectively block the PD-1 checkpoint of T-cells for preventing T-cell exhaustion. Furthermore, in vivo studies reveal the immunological memory effect is significantly elicited in mice received bmNPs therapy. Collectively, bmNPs show great potential in photothermal-enhanced immunotherapy.

Multifunctional nanoparticles potentiate in-situ tumor vaccines via reversing insufficient Photothermal therapy by disrupting tumor vasculature

Photothermal therapy can trigger immunogenic cell death and release personalized in-situ tumor vaccine, activating immune responses to eliminate systemic tumors beyond the irradiated zone. However, the immune response of the in-situ tumor vaccines is often undermined by the residual tumor cells and their induced immunosuppressive tumor microenvironment (TME), which is attributed to insufficient photothermal effects stemming from the limited accumulation of photosensitizers. To overcome these limitations, we developed multi-functional nanoparticles (VI@Gd-NPs) that integrate a tumor vasculature-specific disrupting agent (Vadimezan, Phase III clinical drug), a photosensitizer (Indocyanine Green, ICG), and a magnetic resonance imaging contrast agent (Gadolinium, Gd) through chemical self-assembly. By selectively disrupting the tumor vasculature, these nanoparticles enhance the intratumoral delivery of photosensitizers (ICG and blood cells), and Gd. With the guidance of Gd-enhanced MRI, the improved delivery facilitates comprehensive photothermal ablation and regulates the TME, further initiating the in-situ tumor vaccine. Notably, this approach significantly enhances anti-tumor immune responses, improves survival rates, and reduces tumor recurrence and metastasis in various animal models. Moreover, depleting CD8+ T cells reverses these therapeutic benefits, highlighting the critical role of adaptive T cell immunity. Therefore, the VI@Gd-NPs treatment holds great potential for reigniting the in-situ tumor vaccine of photothermal therapy.

Cancer cell-selective induction of mitochondrial stress and immunogenic cell death by PT-112 in human prostate cell lines

PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study.

Development of an Intracellular Nitric Oxide-Donating Cell-Penetrating Polypeptide as an Immunogenic Cell Death Inducer.

Recently, nitric oxide (NO) has been shown to induce immunogenic cell death (ICD) in tumor cells through endoplasmic reticulum (ER) stress and mitochondrial outer membrane permeabilization (MOMP). However, NO is unstable, making direct delivery difficult. In this study, we developed a cell-penetrating polypeptide-based NO donor, poly(l-guanidine) (PLG). Given that the guanidine structure can be catalyzed by reactive oxygen species (ROS) to produce NO, helical PLG plays three roles: spontaneous cell penetration, intracellular ROS generation to produce NO, and induction of ICD. The results revealed that helical PLG generates NO inside the cell by self-inducible guanidine oxidation and that NO effectively elicits ICD by ER stress- and MOMP-dependent intertwined mechanisms.

Cabozantinib-encapsulated and maytansine-conjugated high-density lipoprotein for immunotherapy in colorectal cancer

Advanced colorectal cancer (CRC) responds poorly to current adjuvant therapies, partially due to its immunosuppressive intestinal microenvironment. We found that myeloid-derived suppressor cells (MDSCs) were enriched in orthotopic tumors due to treatment-induced succinate release, which activated tuft cells and upregulated interleukin 25 (IL-25) and interleukin 13 (IL-13). We engineered a cabozantinib (Cabo)-encapsulated and maytansine (DM1)-conjugated synthetic high-density lipoprotein (ECCD-sHDL) to modulate the tumor microenvironment. DM1 induced immunogenic cell death and promoted the maturation of dendritic cells. Meanwhile, Cabo alleviated DM1-induced succinate release, preventing tuft cell activation, downregulating IL-25 and IL-13 secretion, and reducing intratumoral MDSC infiltration. ECCD-sHDL increased the densities of active cytotoxic T lymphocytes (CTLs) and M1 macrophages in the tumors, effectively inhibiting tumor growth and metastasis, thereby prolonging survival in murine CRC models. Our study sheds light on the mechanism of treatment-induced immunosuppression in orthotopic CRC and demonstrates that this combinatorial therapy could be an effective treatment for CRC.

PAMAM-Based Polymeric Immunogenic Cell Death Inducer To Potentiate Cancer Immunotherapy.

Immunogenic cell death (ICD) has been widely employed to potentiate cancer immunotherapy due to its capability to activate the anticancer immune response. Although various ICD inducers have been described, the development of synthetic materials with intrinsic ICD-inducing competency has rarely been reported. Herein, we identify a derivative of the fourth generation polyamidoamine (PAMAM) modified with multiple seven-membered heterocyclic rings, G4P-C7A, as a robust ICD inducer. G4P-C7A evokes characteristic release of damage-associated molecular patterns in tumor cells and induces efficient dendritic cell maturation. Mechanistic studies suggest that G4P-C7A can selectively accumulate in the endoplasmic reticulum and mitochondria to generate reactive oxygen species. G4P-C7A-treated tumor cells can work as potent vaccines to protect against secondary tumor implantation. Either local or systemic injection of G4P-C7A alone can effectively inhibit tumor growth by eliciting robust antitumor immune response. The combination of G4P-C7A with immunotherapeutic antibodies such as anti-PD1 (aPD-1) and anti-CD47 (aCD47) further potentiates the antitumor effect in either CT26 or 4T1 tumor model. This study offers a simple but effective strategy to induce ICD to boost cancer immunotherapy.

Biomimetic polymeric nanoreactors with photooxidation-initiated therapies and reinvigoration of antigen-dependent and antigen-free immunity

Immune cell-mediated anticancer modalities usually suffer from immune cell exhaustion and limited efficacy in solid tumors. Herein, the oxygen-carrying biomimetic nanoreactors (BNR2(O2)) have been developed with photooxidation-driven therapies and antigen-dependent/antigen-free immune reinvigoration against xenograft tumors. The BNR2(O2) composes polymeric nanoreactors camouflaged with cancer cell membranes can efficiently target homotypic tumors. It continuously releases O2 to boost intracellular reactive oxygen species (ROS) to oxide diselenide bonds, which controllably releases seleninic acids and anti-folate Pemetrexed compared to hydrogen peroxide and glutathione incubation. The O2-rich microenvironment sensitizes Pemetrexed and blocks programmed cell-death ligand 1 (PD-L1) to reverse T cell immunosuppression. The ROS and Pemetrexed upregulate pro-apoptosis proteins and inhibit folate-related enzymes, which cause significant apoptosis and immunogenic cell death to stimulate dendritic cell maturation for improved secretion of cytokines, expanding antigen-dependent T cell immunity. Furthermore, by regulating the release of seleninic acids, the checkpoint receptor human leukocyte antigen E of tumor cells can be blocked to reinvigorate antigen-free natural killer cell immunity. This work offers an advanced antitumor strategy by bridging biomimetic nanoreactors and modulation of multiple immune cells.

Engineering cell membrane-camouflaged COF-based nanosatellite for enhanced tumor-targeted photothermal chemoimmunotherapy

Dendritic cells (DCs) activation is crucial for regulating the antitumor immune response. However, the tumor's immunosuppressive environment significantly impedes antigen presentation and DCs maturation, thereby limiting the effectiveness of cancer immunotherapy. To address this challenge, we developed tumor cell membrane-coated covalent organic framework (COF) nanoparticles, loaded with mannose-modified gold nanoparticles and doxorubicin (Dox). This created a cell membrane-camouflaged COF-based nanosatellite designed to enhance tumor-targeted chemoimmunotherapy. The nanosatellite exhibits distinct photothermal properties and releases Dox in a pH-sensitive manner, targeting tumor cells to induce immunogenic cell death (ICD) and expose a wealth of antigens. Crucially, the COF structure is selectively degraded to release mannose-modified gold nanoparticles in the acidic environment. These nanoparticles capture antigens from the ICD and efficiently transport them to lymph nodes rich in DCs, facilitated by mannose receptor mediation. As a result, antigens are effectively presented to DCs, activating the immune response, significantly hindering tumor growth and lung metastasis in mice, and extending survival. This study pioneered innovative nano-preparations aimed at enhancing tumor immunotherapy.

Multi-Enzyme Nanoparticles as Efficient Pyroptosis and Immunogenic Cell Death Inducers for Cancer Immunotherapy.

Immunotherapy represents a widely employed modality in clinical oncology, leveraging the activation of the human immune system to target and eradicate cancer cells and tumor tissues via endogenous immune mechanisms. However, its efficacy remains constrained by inadequate immune responses within "cold" tumor microenvironment (TME). In this study, a multifunctional nanoscale pyroptosis inducer with cascade enzymatic activity (IMZF), comprising superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), is dissociated within the acidic and glutathione-rich TME. The vigorous enzymatic activity not only generates oxygen (O2) to alleviate hypoxia and promote M2 to M1 macrophage polarization but also yields reactive oxygen species (ROS) and depletes glutathione (GSH) within the TME. Functioning as an immunogenic cell death (ICD) activator and pyroptosis inducer, IMZF synergistically triggers dendritic cell maturation and inflammatory lymphocyte infiltration via ICD-associated pyroptosis, thereby reversing immune suppression within the TMEs. Consequently, it exerts inhibitory effects on both primary and distal tumors. This cascade enzymatic platform-based pyroptosis inducer offers an intelligent strategy for effectively overcoming immune suppression within "cold" tumors, thereby providing a promising avenue for advanced immunotherapeutic interventions.

Revealing the mechanism of natural product-induced immunogenic cell death: opening a new chapter in tumor immunotherapy.

This review underscores the role of natural products in inducing immunogenic cell death (ICD) as a key strategy in tumor immunotherapy. It reveals that natural products can activate ICD through multiple pathways-apoptosis, autophagy, pyroptosis, and necroptosis-leading to the release of danger-associated molecular patterns (DAMPs), dendritic cell activation, and improved antigen presentation, which together stimulate a potent anti-tumor immune response. The study also demonstrates the enhanced therapeutic potential of combining natural products with immune checkpoint inhibitors. With a focus on translating preclinical findings into clinical practice, this review consolidates recent discoveries and suggests future research paths, offering both theoretical insights and practical guidance for advancing cancer immunotherapy.

Mobilizing STING Pathway via a Cationic Liposome to Enhance Doxorubicin‐Induced Antitumor Immunity

AbstractThe efficacy of anthracycline, such as doxorubicin (DOX), is facilitated by cancer cell‐intrinsic type I interferon (IFN‐I) signaling through the induction of immune responses. However, weak and chronic IFN‐I responses from rounds of chemotherapy lead to resistance against DNA damage and acquired resistance to the therapy. An exogenous supply of IFN‐I can improve the chemotherapeutic responses. Herein, a library of cationic liposomes is developed for the optimization of 1, 2‐dioleoyl‐3‐trimethylammonium‐propane (DOTAP) proportions to enhance the lysosome escape and tumor distribution of the stimulator of interferon genes (STING) agonist 2′,3′‐cyclic guanosine monophosphate‐adenosine monophosphate (cGAMP) and DOX. The cationic liposomes with 8% DOTAP release cGAMP into the cytoplasm and increase the concentration of DOX in the tumor by 1.5 times compared with the free drug. Upon accumulation at the tumor site, the optimized liposomes induce immunogenic cell death (ICD) and stimulate the STING signaling, thereby improving the production of endogenous IFN‐I and promoting dendritic cell maturation to mobilize T cell immunity. The tumor growth inhibition rate is 86%, and the median survival time is 1.6‐fold prolonged. This study offers a strategy to enhance the DOX‐induced immune response by activating the STING pathway to supply IFN‐I.

Sonocatalysis Regulates Tumor Autophagy for Enhanced Immunotherapy.

Immunotherapy stands as a groundbreaking strategy for cancer treatment, due to its ability to precisely and safely detect and eradicate tumors. However, the efficacy of immunotherapy is often limited by tumor autophagy, a natural defense mechanism that tumors exploit to resist immune attacks. Herein, we introduce a spatiotemporally controlled method to modulate tumor autophagy via sonocatalysis, aiming to improve immunotherapeutic outcomes. Specifically, we synthesized a tumor-targeting nanocatalyst based on a semiconductor heterojunction composed of Barium Titanate (BTO), Black Phosphorus (BP) integrated with Hyaluronic Acid (HA), referred to as BTO/BP-HA. Compared to traditional catalysts, the heterojunction structure enhances energy band bending and rapid electron-hole separation under ultrasonic stimulation, splitting water to generate H2. This promotes tumor cell apoptosis by inhibiting mitochondrial respiration and induces immunogenic cell death, triggering immune responses to eliminate tumor cells. However, the concurrent activation of autophagy mitigates the cytotoxic effectiveness of nanocatalysts. Within the nanocatalyst, BP undergoes lysosomal degradation to generate PO43-, which subsequently interacts with H+ to generate a conjugated acidic anion, increasing the lysosomal pH. This research ingeniously combines sonocatalysis with tumor autophagy, disrupting the activity of acidic hydrolases to inhibit autophagy, thereby enhancing the immune response and improving the effectiveness of immunotherapy.

Two-dimensional coordination risedronate-manganese nanobelts as adjuvant for cancer radiotherapy and immunotherapy

The irradiated tumor itself represents an opportunity to establish endogenous in situ vaccines. However, such in situ cancer vaccination (ISCV) triggered by radiation therapy (RT) alone is very weak and hardly elicits systemic anticancer immunity. In this study, we develop two-dimensional risedronate-manganese nanobelts (RMn-NBs) as an adjuvant for RT to address this issue. RMn-NBs exhibit good T2 magnetic resonance imaging performance and enhanced Fenton-like catalytic activity, which induces immunogenic cell death. RMn-NBs can inhibit the HIF-1α/VEGF axis to empower RT and synchronously activate the cGAS/STING pathway for promoting the secretion of type I interferon, thereby boosting RT-triggered ISCV and immune checkpoint blockade therapy against primary and metastatic tumors. RMn-NBs as a nano-adjuvant for RT show good biocompatibility and therapeutic efficacy, presenting a promising prospect for cancer radiotherapy and immunotherapy.

Present Scenario and Future Landscape of Payloads for ADCs: Focus on DNA-Interacting Agents

ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index. Some of these molecules, however, continue to be of interest due to their favorable properties in terms of cytotoxic potency even in chemoresistant settings, bystander and immunogenic cell death effects, and known combinability with approved drugs. We critically evaluated several clinically tested ADCs containing DNA binders, focusing on payload physicochemical properties, cytotoxic potency, and obtained clinical results. Our analysis suggests that further exploration of certain chemical classes, specifically anthracyclines and duocarmycins, based on the optimization of physicochemical parameters, reduction of cytotoxic potency, and careful design of targeting molecules is warranted. This approach will possibly result in a novel generation of payloads overcoming the limitations of clinically validated ADCs.

Identification and validation of diagnostic markers related to immunogenic cell death and infiltration of immune cells in diabetic nephropathy

IntroductionImmunogenic cell death (ICD) is a unique cell death triggered by chemotherapy. However, studies elucidating the potential therapeutic role of ICD and the underlying mechanism in diabetic nephropathy (DN) are limited. MethodsWGCNA was conducted on the human kidney biopsy data linked to DN, analyzing gene sets associated with ICD. Gene Set Enrichment Analysis and Gene Set Variation Analysis were utilized to examine the discrepancy in biological function. We used Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, and the GeneMANIA database to investigate the function of the signature genes. An analysis using the receiver operating characteristic (ROC) was conducted to validate the diagnostic value of hub genes. Additionally, immune infiltration-related analyses were also performed. In conclusion, we examined the association between the glomerular filtration rate, serum creatinine, and hub genes. Hub genes were validated by immunohistochemistry using db/db mice kidneys. ResultsWGCNA revealed that the targets in the turquoise unit (1674 genes) exhibited the highest positive correlation with ICD. Furthermore, 4222 statistically significant DEGs were identified when comparing the DN and healthy control groups. Significantly, the KEGG pathway enrichment analysis indicated a connection between ICD and the nuclear factor-kappa B signaling pathway and the synthesis of cytokines (tumor necrosis factor superfamily). ROC analysis revealed that 16 hub genes exhibited strong discriminatory potential as biomarkers for DN. Therefore, immunohistochemical validation, with the potential involvement of chemokines (CCL11, CCR2, CCR7, CX3CR1, CXCL10, CXCL12, and CXCR5) and immune cells (CD3G, CD5, and CD247) may be crucial for the diagnosis and therapy of DN. ConclusionsDKK3, NR4A1, NR4A2, VEGFA, and DUSP1 may be associated with the development of DN. The pathogenesis of DN may specifically involve chemokines (CCL11, CCR2, CCR7, CX3CR1, CXCL10, CXCL12, and CXCR5) and immune cells (CD3G, CD5, and CD247), with LCP2 playing a significant role.

Induced Necroptosis and Its Role in Cancer Immunotherapy

Necroptosis is a type of regulated cell death (RCD) that is triggered by changes in the extracellular or intracellular milieu that are picked up by certain death receptors. Thanks to its potent capacity to induce immunological responses and overcome apoptotic resistance, it has garnered significant attention as a potential cancer treatment. Basic information for the creation of nano-biomedical treatments is provided by studies on the mechanisms underlying tumor necroptosis. Receptor-interacting protein kinase 1 (RIPK1)–RIPK3-mediated necroptosis, Toll-like receptor domain-containing adapter-inducing interferon (IFN)-β (TRIF)–RIPK3-mediated necroptosis, Z-DNA-binding protein 1 (ZBP1)–RIPK3-mediated necroptosis, and IFNR-mediated necroptosis are the four signaling pathways that collectively account for triggered necroptosis in this review. Necroptosis has garnered significant interest as a possible cancer treatment strategy because, in contrast to apoptosis, it elicits immunological responses that are relevant to therapy. Thus, a thorough discussion is held on the connections between tumor cell necroptosis and the immune environment, cancer immunosurveillance, and cells such as dendritic cells (DCs), cytotoxic T cells, natural killer (NK) cells, natural killer T (NKT) cells, and their respective cytokines. Lastly, a summary of the most recent nanomedicines that cause necroptosis in order to cause immunogenic cell death is provided in order to emphasize their promise for cancer immunotherapy.

Induction of immunogenic cell death and enhancement of the radiation-induced immunogenicity by chrysin in melanoma cancer cells

Chrysin is a natural flavonoid with anti-cancer effects. Despite its beneficial effects, little information is available regarding its immunogenic cell death (ICD) properties. In this work, we hypothesized that chrysin can potentiate radiotherapy(RT)-induced immunogenicity in melanoma cell line (B16-F10). We examined the effects of chrysin alone and in combination with radiation on ICD induction in B16-F10 cells. Cell viability was assessed using an MTT assay. Cell apoptosis and calreticulin (CRT) exposure were determined using flow cytometry. Western blotting and ELISA assay were employed to examine changes in protein expression. Combination therapy exhibited a synergistic effect, with an optimum combination index of 0.66. The synergistic anti-cancer effect correlated with increased cell apoptosis in cancer cells. Compared to the untreated control, chrysin alone and in combination with RT induced higher levels of DAMPs, such as CRT, HSP70, HMGB1, and ATP. The protein expression of p-STAT3/STAT3 and PD-L1 was reduced in B16-F10 cells exposed to chrysin alone and in combination with RT. Conditioned media from B16-F10 cells exposed to mono-and combination treatments elicited IL-12 secretion in dendritic cells (DCs), inducing a Th1 response. Our findings revealed that chrysin could induce ICD and intensify the RT-induced immunogenicity.