Immunogenic Cell Death Research Articles

Dual-responsive natural killer cell nano-engagers for cancer immunotherapy via inhibiting IL-6/JAK2/STAT3 pathway

Natural killer (NK) cell-based immunotherapy is a promising approach for treating solid tumors and hematological malignancies. However, its therapeutic efficacy is limited by poor tumor infiltration and suppressive tumor microenvironment. Here, we introduce a rapid, simple, and efficient solution: bovine serum albumin-stabilized ultra-small (4 nm) NK cell nano-engagers, termed Bi2Se3@BSA nanodots (Nds). These Nds, responsive to high H2O2 levels in tumor cell environments, enhance near-infrared (NIR)-II photothermic immunotherapy. In vitro and in vivo experiments demonstrate their effectiveness in activating photothermal therapy (PTT)-induced immunogenic cell death (ICD), initiating immune cascade reactions, and stimulating immune response activation. By upregulating NKG2D, RAE-1, and secreting cytokines such as IFN-γ and TNF-α, targeted NK cell infiltration is achieved, reversing the immunosuppressive tumor microenvironment and optimizing NK cell cytotoxicity. Transcriptomic analysis confirms the association of immune response activation with the IL-6/JAK2/STAT3 signaling pathway. Notably, combining these nano-engagers with immune checkpoint inhibitors (aPD-1) significantly enhances therapeutic efficacy, facilitating tumor eradication and reducing recurrence risk. Taken together, NK cell nano-engagers inhibit the IL-6/JAK2/STAT3 signaling pathway, target NK cell activation, stimulate immune functions, and improve the immunosuppressive microenvironment. This study presents an alternative strategy for NK cell-based immunotherapy and highlights this promising tool for cancer immunotherapy.

Polymeric nanocarrier via metabolism regulation mediates immunogenic cell death with spatiotemporal orchestration for cancer immunotherapy

The limited efficacy of cancer immunotherapy occurs due to the lack of spatiotemporal orchestration of adaptive immune response stimulation and immunosuppressive tumor microenvironment modulation. Herein, we report a nanoplatform fabricated using a pH-sensitive triblock copolymer synthesized by reversible addition-fragmentation chain transfer polymerization enabling in situ tumor vaccination and tumor-associated macrophages (TAMs) polarization. The nanocarrier itself can induce melanoma immunogenic cell death (ICD) via tertiary amines and thioethers concentrating on mitochondria to regulate metabolism in triggering endoplasmic reticulum stress and upregulating gasdermin D for pyroptosis as well as some features of ferroptosis and apoptosis. After the addition of ligand cyclic arginine-glycine-aspartic acid (cRGD) and mannose, the mixed nanocarrier with immune adjuvant resiquimod encapsulation can target B16F10 cells for in situ tumor vaccination and TAMs for M1 phenotype polarization. In vivo studies indicate that the mixed targeting nanoplatform elicits tumor ICD, dendritic cell maturation, TAM polarization, and cytotoxic T lymphocyte infiltration and inhibits melanoma volume growth. In combination with immune checkpoint blockade, the survival time of mice is markedly prolonged. This study provides a strategy for utilizing immunoactive materials in the innate and adaptive immune responses to augment cancer therapy.

PARP inhibitors enhance antitumor immune responses by triggering pyroptosis via TNF–caspase 8–GSDMD/E axis in ovarian cancer

BackgroundIn addition to their established action of synthetic lethality in tumor cells, poly(ADP-ribose) polymerase inhibitors (PARPis) also orchestrate tumor immune microenvironment (TIME) that contributes to suppressing tumor growth. However, it...

Photo-Amplified Plasma Membrane Rupture by Membrane-Anchoring NIR-II Small Molecule Design for Improved Cancer Photoimmunotherapy.

Immunotherapy is a promising cancer treatment method for eradicating tumor cells by enhancing the immune response. However, there are several major obstacles to conventional phototherapy-mediated immune responses, including inadequate immunogenicity and immunosuppressive environment. Here, we present a novel photoimmunotherapy modality-the development of membrane-anchoring small molecule inducing plasma membrane rupture (PMR) by NIR-II photo-stimulation, thus evoking cell necrotic death and enhancing antitumor immunotherapy. Our top-performing membrane-anchoring small molecule (CBT-3) exhibits temperature-tunable PMR efficiency, allowing rapid necrotic death in cancer cells at 50 μM dose by using exogenous NIR-II light-mediated mild photothermal effect (1064 nm, 0.6 W cm-2). Further evidence indicated that this gentle therapeutic approach activated inflammatory signaling pathways in cells, enhanced immunogenic cell death, and reshaped the immunosuppressive tumor microenvironment, ultimately promoting systemic antitumor immune responses in vivo. This study represents the first instance of utilizing NIR-II photo-amplified PMR effect based on membrane-anchoring small molecule, providing a novel avenue for advancing cancer photoimmunotherapy.

Recurrent pancreatic cancer treated with N-803 and PD-L1 t-haNK followed by an EGFR-targeted nanocell drug conjugate.

Multimodal temporal therapy orchestrated to leverage immunotherapy, tumor-targeted chemotherapy, and natural killer (NK) cell therapy may provide an opportunity to induce immunogenic cell death for tumor response and increased survival in patients with recurrent cancer. The interleukin-15 (IL-15) superagonist N-803, an enhancer of NK cells, CD4 + T cells, cytotoxic CD8 + T cells, and memory T-cell activity, combined with off-the-shelf PD-L1-targeted high-affinity NK (PD-L1 t-haNK) cells represent novel immunotherapies designed to overcome an immunosuppressive tumor microenvironment (TME). The epidermal growth factor receptor-targeted antibody-nanocell conjugate E-EDV-D682 provides tumor-targeted chemotherapy in the form of its anthracycline metabolite PNU159682 (nemorubicin) cargo and is currently being studied in combination with immunomodulatory EDVs delivering the adjuvant α-galactosyl ceramide (GC). Here, we report the compassionate use treatment of this combination in a patient with recurrent, metastatic pancreatic cancer (mPC) after 3 lines of therapy. Under the initial single-patient Investigational New Drug (spIND) protocol, the patient received N-803, PD-L1 t-haNK cells, and the albumin doxorubicin conjugate aldoxorubicin for ~27 months. The patient's disease became stable on this regimen, and a transient complete response was observed by ~14 months of therapy. Due to progression, a second spIND protocol was designed whereby the patient received E-EDV-D682 plus EDV-GC for more than 24 months, which resulted in stable disease and the patient's continued survival at the time this report was written. The patient's extended survival despite the dire prognosis associated with recurrent mPC points to the merits of this temporal combination regimen in overcoming immuno-chemo resistance with enhanced immune activity required for tumor response and extended survival.

Tumor microenvironment-activated polypeptide nanoparticles for oncolytic immunotherapy

Cationic oncolytic polypeptides have gained increasing attention owing to their ability to directly lyse cancer cells and activate potent antitumor immunity. However, the low tumor cell selectivity and inherent toxicity induced by positive charges of oncolytic polypeptides hinder their systemic application. Herein, a tumor microenvironment-responsive nanoparticle (DNP) is developed by the self-assembly of a cationic oncolytic polypeptide (PLP) with a pH-sensitive anionic polypeptide via electrostatic interactions. After the formation of DNP, the positive charges of PLP are shielded. DNPs can keep stable in physiological conditions (pH 7.4) but respond to acidic tumor microenvironment (pH 6.8) to release oncolytic PLP. As a result, DNPs evoke potent immunogenic cell death by disrupting cell membranes, damaging mitochondria and increasing intracellular levels of reactive oxygen species. In vivo results indicate that DNPs significantly improve the biocompatibility of PLP, and inhibit tumor growth, recurrence and metastasis by direct oncolysis and activation of antitumor immune responses. In summary, these results indicate that pH-sensitive DNPs represent a prospective strategy to improve the tumor selectivity and biosafety of cationic polymers for oncolytic immunotherapy.

Branched oncolytic peptides target HSPGs, inhibit metastasis, and trigger the release of molecular determinants of immunogenic cell death in pancreatic cancer.

Immunogenic cell death (ICD) can be exploited to treat non-immunoreactive tumors that do not respond to current standard and innovative therapies. Not all chemotherapeutics trigger ICD, among those that do exert this effect, there are anthracyclines, irinotecan, some platinum derivatives and oncolytic peptides. We studied two new branched oncolytic peptides, BOP7 and BOP9 that proved to elicit the release of damage-associated molecular patterns DAMPS, mediators of ICD, in pancreatic cancer cells. The two BOPs selectively bound and killed tumor cells, particularly PANC-1 and Mia PaCa-2, but not cells of non-tumor origin such as RAW 264.7, CHO-K1 and pgsA-745. The cancer selectivity of the two BOPs may be attributed to their repeated cationic sequences, which enable multivalent binding to heparan sulfate glycosaminoglycans (HSPGs), bearing multiple anionic sulfation patterns on cancer cells. This interaction of BOPs with HSPGs not only fosters an anti-metastatic effect in vitro, as demonstrated by reduced adhesion and migration of PANC-1 cancer cells, but also shows promising tumor-specific cytotoxicity and low hemolytic activity. Remarkably, the cytotoxicity induced by BOPs triggers the release of DAMPs, particularly HMGB1, IFN-β and ATP, by dying cells, persisting longer than the cytotoxicity of conventional chemotherapeutic agents such as irinotecan and daunorubicin. An in vivo assay in nude mice showed an encouraging 20% inhibition of tumor grafting and growth in a pancreatic cancer model by BOP9.

Immunogenic cell death signatures from on-treatment tumor specimens predict immune checkpoint therapy response in metastatic melanoma

Melanoma is a highly malignant form of skin cancer that typically originates from abnormal melanocytes. Despite significant advances in treating metastatic melanoma with immune checkpoint blockade (ICB) therapy, a substantial number of patients do not respond to this treatment and face risks of recurrence and metastasis. This study collected data from multiple datasets, including cohorts from Riaz et al., Gide et al., MGH, and Abril-Rodriguez et al., focusing on on-treatment samples during ICB therapy. We used the single-sample gene set enrichment analysis (ssGSEA) method to calculate immunogenic cell death scores (ICDS) and employed an elastic network algorithm to construct a model predicting ICB efficacy. By analyzing 18 ICD gene signatures, we identified 9 key ICD gene signatures that effectively predict ICB treatment response for on-treatment metastatic melanoma specimens. Results showed that patients with high ICD scores had significantly higher response rates to ICB therapy compared to those with low ICD scores. ROC analysis demonstrated that the AUC values for both the training and validation sets were around 0.8, indicating good predictive performance. Additionally, survival analysis revealed that patients with high ICD scores had longer progression-free survival (PFS). This study used an elastic network algorithm to identify 9 ICD gene signatures related to the immune response in metastatic melanoma. These gene features can not only predict the efficacy of ICB therapy but also provide references for clinical decision-making. The results indicate that ICD plays an important role in metastatic melanoma immunotherapy and that expressing ICD signatures can more accurately predict ICB treatment response and prognosis for on-treatment metastatic melanoma specimens, thus providing a basis for personalized treatment.

Reshaped Local and Systemic Immune Responses Triggered by a Biomimetic Multifunctional Nanoplatform Coordinating Multi-Pathways for Cancer Therapy.

Immunotherapy has fundamentally transformed the clinical cancer treatment landscape; however, achieving intricate and multifaceted modulation of the immune systems remains challenging. Here, a multipathway coordination of immunogenic cell death (ICD), autophagy, and indoleamine 2,3-dioxygenase-1 (IDO1) was achieved by a biomimetic nano-immunomodulator assembled from a chemotherapeutic agent (doxorubicin, DOX), small interfering RNA (siRNA) molecules targeting IDO1 (siIDO1), and the zeolitic imidazolate framework-8 (ZIF-8). After being camouflaged with a macrophage membrane, the biomimetic nanosystem, named mRDZ, enriched in tumors, which allowed synergistic actions of its components within tumor cells. The chemotherapeutic intervention led to a compensatory upregulation in the expression of IDO1, consequently exerting an inhibitory effect on the reactive oxygen species (ROS) and autophagic responses triggered by DOX and ZIF-8. Precise gene silencing of IDO1 by siIDO1 alleviated its suppressive influence, thereby facilitating increased ROS production and improved autophagy, ultimately bolstering tumor immunogenicity. mRDZ exhibited strong capability to boost potent local and systemic antitumor immune responses with a feature of memory, which led to the effective suppression of the growth, lung metastasis, and recurrence of the tumor. Serving as an exemplary model for the straightforward and potent reshaping of the immune system against tumors, mRDZ offers valuable insights into the development of immunomodulatory nanomaterials for cancer therapy.

Lysosome Targeted Nanoparticle Aggregation Reverses Immunosuppressive Tumor Microenvironment for Cancer Immunotherapy.

Nanotechnology has proven its enormous application value in clinical practice. However, current research on nanomedicines mainly focuses on developing nanoparticles as delivery carriers to maximize the bioavailability of therapeutic agents, with little attention on exploring their potential to directly regulate physiological processes. In this study, inspired by the lysosomal swelling caused by excessive accumulation of undegraded substances, this work presents a lysosomal-targeting aggregated nanoparticle (LTANP) for cancer treatment. By rationally engineering surface composition, properties, and interparticle interactions, LTANP achieves efficient tumor accumulation and selective targeted aggregation in lysosomes of cancer cells, leading to unrelievable lysosomal swelling, and ultimately inducing lysosomal membrane permeabilization (LMP) of cancer cells. Further analysis shows that nanoparticle aggregation-mediated LMP can effectively trigger immunogenic cell death (ICD) by impairing autophagy-lysosome pathway, evoking robust antitumor immune responses and reversing tumor immunogenicity from "cold" to "hot" in a melanoma model. Additionally, LTANP can combine with clinically approved programmed death ligand-1 (PD-L1) antibodies to further unleash T cell-mediated antitumor immunity, significantly enhancing antitumor performance, inhibiting tumor recurrence and metastasis. This work demonstrates the potential of rationally engineered nanostructures in directly combating cancer and provides novel insights for the development of advanced nanoparticle-based cancer treatment.

Reprogramming the Tumor Immune Microenvironment Through Activatable Photothermal Therapy and GSH depletion Using Liposomal Gold Nanocages to Potentiate Anti-Metastatic Immunotherapy.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.

Enhancing CAR-T cell therapy against solid tumor by drug-free triboelectric immunotherapy

Chimeric antigen receptor (CAR) T cell therapy is a highly effective immunotherapy for hematological tumors, but its efficacy against most solid tumors remains challenging. Herein, a novel synergistic combination therapy of drug-free triboelectric immunotherapy and CAR-T cell therapy against solid tumor was proposed. A triboelectric nanogenerator (TENG) that can generate pulsed direct-current by coupling triboelectrification effect and electrostatic breakdown effect was fabricated. The TENG can generate up to 30 pulse direct-current peaks with peak current output ≈35 μA in a single sliding to power the triboelectric immunotherapy. The pulsed direct-current stimulation induced immunogenic cell death of tumor cells (survival rate of 35.9 %), which promoted dendritic cells maturation, accelerated the process of antigen presentation to CAR-T cells and enhanced the systemic adaptive immune response. Furthermore, triboelectric immunotherapy promoted M1-like macrophage polarization, reduced regulatory T cells differentiation and reprogrammed the tumor immunosuppressive microenvironment, which ultimately enhanced the efficacy of CAR-T cells to eradicate nearly 60 % of NALM6 solid tumor mass. Notably, considering that triboelectric immunotherapy is a safe and effective drug-free antitumor strategy, the combined therapy did not increase the burden of double-medication on patients.

PAD4 Inhibitor-Loaded Layered Double Hydroxide Nanosheets as a Multifunctional Nanoplatform for Photodynamic Therapy-Mediated Tumor Metastasis Treatment.

Photodynamic therapy (PDT) is demonstrated to be effective in inducing antitumor immune responses for tumor metastasis treatment. However, tumor hypoxia, inferior tissue penetration of light, and low singlet oxygen (1O2) quantum yield significantly hamper the efficacy of PDT, thus weakening its immune function. Moreover, PDT-mediated neutrophil extracellular traps (NETs) formation can further reduce the therapeutic effectiveness. Herein, the use of defect-rich CoMo-layered double hydroxide (DR-CoMo-LDH) nanosheets as a carrier to load a typical peptidyl arginine deiminase 4 inhibitor, i.e., YW4-03, to construct a multifunctional nanoagent (403@DR-LDH) for PDT/immunotherapy, is reported. Specifically, 403@DR-LDH inherits excellent 1O2 generation activity under 1550nm laser irradiation and improves the half-life of YW4-03. Meanwhile, 403@DR-LDH plus 1550nm laser irradiation can stimulate immunogenic cell death to promote the maturation of dendric cells and activation/infiltration of T cells and significantly downregulate H3cit protein expression to inhibit NETs formation, synergistically promoting the antitumor metastasis effect. Taken together, 403@DR-LDH can kill cancer cells and inhibit tumor growth/metastasis under 1550nm laser irradiation. Single-cell analysis indicates that 403@DR-LDH can regulate the ratio of immune cells and immune-related proteins to improve the tumor immune microenvironment, showing strong efficacy to inhibit the tumor growth, metastasis, and recurrence.

Biomimetic Nanomodulators With Synergism of Photothermal Therapy and Vessel Normalization for Boosting Potent Anticancer Immunity.

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC).

Sulfate Radical Based In Situ Vaccine Boosts Systemic Antitumor Immunity via Concurrent Activation of Necroptosis and STING Pathway.

In situ vaccine (ISV) can provoke systemic anti-tumor immunity through the induction of immunogenic cell death (ICD). The development of ISV technology has been restricted by the limited and suboptimal ICD driven tumor antigen production which are currently relying on chemo-drugs, photo-/radio-sensitizers, oncolytic-virus and immunostimulatory agents. Herein, a sulfate radical (SO4 ·-) based ISV is reported that accomplishes superior tumor immunotherapy dispense from conventional approaches. The ISV denoted as P-Mn-LDH is constructed by intercalating peroxydisulfate (PDS, a precursor of SO4 ·-) into manganese layered double hydroxide nanoparticles (Mn-LDH). This design allows the stabilization of PDS under ambient condition, but triggers a Mn2+ mediated PDS decomposition in acidic tumor microenvironment (TME) to generate in situ SO4 ·-. Importantly, it is found that the SO4 ·- radicals not only effectively kill cancer cells, but also induce a necroptotic cell death pathway, leading to robust ICD signaling for eliciting adaptive immunity. Further, the P-Mn-LDH can activate the stimulator of interferon genes (STING) pathway to further boost anti-tumor immunity. Collectively, the P-Mn-LDH based ISV exhibited potent activity in inhibiting tumor growth and lung metastasis. When combined with immune checkpoint inhibitor, significant inhibition of distant tumors is achieved. This study underpins the promise of SO4 ·- based vaccine technology for cancer immunotherapy.

Injectable hydrogel assisted formation of hydroxyl radical generating bioreactor enables photothermally enhanced chemodynamic and immunotherapy

Photothermal therapy and chemodynamic therapy (CDT), two recently invented cancer treatments, have shown to be effective in potentiating immunotherapy through causing immunogenic cancer cell death. The rational integration of these two therapeutic modalities poses a formidable challenge in eliciting robust immunotherapy. Herein, an injectable hydrogel based bioreactor comprising of glucose oxidase (GOx), copper sulfide (CuS) nanoparticles, and poly (ethylene glycol) double acrylate (PEGDA) is prepared to potentiate immune checkpoint blockade (ICB) therapy. GOx can in situ convert glucose to hydrogen peroxide (H2O2) and gluconic acid, the latter of which further promotes the decomposition of H2O2 to hydroxyl radicals by creating an acidic microenvironment to benefit the pH-dependent Fenton-like catalytic reaction of Cu+, particularly in synergizing with near infrared (NIR) light exposure. Such catalytic couple of GOx and CuS together with NIR light exposure is efficient in inducing immunogenic cancer cell death. Additionally, GOx reprogrammed tumor immunosuppressive microenvironment by reducing lactate levels. Upon being fixed inside tumors with PEGDA hydrogel, such in situ formed bioreactor effectively suppresses the growth of 4T1 orthotopic murine breast cancers in Balb/c mice together with 808 nm laser exposure. Furthermore, such bioreactor enabled photothermally enhanced CDT could also synergize with anti-PD-L1 immunotherapy to more effectively suppress the growth of primary tumors and distant tumors. This study highlights that such NIR light and reactive oxygen species dual responsive bioreactor is robust to potentiate ICB immunotherapy.

A Robust ROS Generation and Ferroptotic Lipid Modulation Nanosystem for Mutual Reinforcement of Ferroptosis and Cancer Immunotherapy.

Ferroptosis initiation is often utilized for synergistic immunotherapy. While, current immunotherapy is limited by an immunosuppressive tumor microenvironment (TME), and ferroptosis is limited by insufficient reactive oxygen species (ROS) and ferroptotic lipids in tumor cells. Here, an arachidonic acid (AA) loaded nanosystem (CTFAP) is developed to mutually reinforce ferroptosis and cancer immunotherapy by augmenting ROS generation and modulating ferroptotic lipids. CTFAP is composed of acid-responsive core calcium peroxide (CaO2) nanoparticles, ferroptotic lipids sponsor AA, tetracarboxylic porphyrin (TCPP) and Fe3+ based metal-organic framework structure, and biocompatible mPEG-DSPE for improved stability. Once endocytosed by tumor cells, CTFAP can release oxygen (O2) and hydrogen peroxide (H2O2) in the acidic TME, facilitating TCPP-based sonodynamic therapy and Fe3+-mediated Fenton-like reactions to generate substantial ROS for cell ferroptosis initiation. The immunogenic cell death (ICD) after ferroptosis promotes interferon γ (IFN-γ) secretion to up-regulate the expression of long-chain family member 4 (ACSL4), cooperating with the released AA from CTFAP to accelerate the accumulation of lipid peroxidation (LPO) and thereby promoting ferroptosis in cancer cells.CTFAP with ultrasound treatment efficiently suppresses tumor growth, has great potential to challenges in cancer immunotherapy.

CaCO3-complexed pH-responsive nanoparticles encapsulating mitoxantrone and celastrol enhance tumor chemoimmunotherapy

Modulating the immunosuppressive tumor microenvironment (TME) while enhancing antitumor immune responses is a promising strategy. In this study, we designed an acid-sensitive nanosystem (MCCaNPs) to demonstrate effective immunotherapy against cancer through the systemic delivery of immune-stimulating chemotherapy combinations. A pH-responsive nanoplatform containing CaCO3 was prepared by the double emulsion method, and mitoxantrone (MIT) and celastrol (CEL) were simultaneously encapsulated as immunogenic cell death (ICD) inducers. Due to the acid responsiveness of CaCO3, the nanoparticles rapidly consume H+ to relieve the acidic tumor microenvironment and explosively release CEL and MIT, showing inherent immunomodulatory activity in collaborative tumor chemoimmunotherapy. MIT and CEL synergistically trigger stronger ICD by inducing tumor cells to release calreticulin (CRT), high mobility group box 1 protein (HMGB1). Following the intravenous administration of MCCaNPs, the local tumor microenvironment(TME) was reprogrammed in mice-bearing tumors. This reprogramming was characterized by a significant increase in the density of tumor-infiltrating cytotoxic T lymphocytes(CTLs), ultimately prolonging survival. Therefore, this research proposes a promising approach to trigger immunogenic cell death collaboratively, aiming to boost the tumor CTLs infiltration for anticancer immunotherapy.

A metabolic intervention strategy for enhanced ferroptosis/cuproptosis activation and boosted anti-tumor immunity

Accumulating evidence suggests that cupreous nanomaterials are capable to trigger the cuproptosis and ferroptosis of malignant cells, providing possibilities for cancer therapy. However, how to realize synchronous cuproptosis and ferroptosis sensitization remains a research gap. Considering the interplays between cuproptotic and ferroptotic pathways, the manipulation of their common regulators provides a feasible approach; based on this, we innovatively propose a metabolic intervention strategy to synchronously reinforce tumor cells’ cuproptosis/ferroptosis susceptibility. STF-31 is utilized to inhibit glycolysis and compensatory nicotinamide adenine dinucleotide (NAD+) metabolism, which is encapsulated in the lipid bilayers of a composited copper (Cu)-tannic acid (TA) network/liposome system. The as-prepared nanosystem (SCu/L) significantly decreases intracellular glucose, NAD+, reduced nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate (ATP) levels and inhibits Cu-ATPase activity, thus inhibiting GSH synthesis and Cu efflux and eventually reinforcing both cuproptosis and ferroptosis. Besides, the glycolysis inhibition effect also helps to remodulate tumor immune microenvironment (TIME), finally boosting anti-tumor immunity together with immunogenic cell death (ICD)-activated T cell immunity. Taken together, this work presents a simple yet effective metabolic intervention strategy for synchronously sensitizing tumor cells to cuproptosis and ferroptosis induced by a cupreous system, providing a feasible pattern for reinforcing the tumoricidal efficiency of cupreous formulations and expanding the prospective applications of ferroptosis/cuproptosis-based therapy.

Combination of Losartan and Platinum Nanoparticles with Photothermal Therapy Induces Immunogenic Cell Death Effective Against Neuroblastoma.

Photothermal therapy (PTT) is a promising therapeutic procedure with minimal side effects, which can not only kill tumor directly but also cause immunogenic cell death (ICD). However, most solid tumors, including neuroblastoma, are abundant in fibroblasts, which limit the penetration and delivery of nanoparticles. Losartan is an antihypertensive drug approved by the FDA, and it has been proved to have the effect of breaking down excessive ECM network. In this study, we investigated the application and potential mechanism of the combination of mesoporous platinum nanoparticles (MPNs) and losartan in the PTT of neuroblastoma by establishing neuroblastoma models in vitro and in vivo. Compared to the MPNs group without 808 nm laser irradiation, Neuro-2a cells pretreated with PTT and losartan showed lower survival rates, increased surface calreticulin, and higher release of HMGB1 and ATP. The group also exhibited the highest anti-tumor efficacy in vivo, with a tumor suppression ratio of approximately 80%. Meanwhile, we found that CD3+ T cells, CD4+ T cells and CD8+ T cells from the peripheral blood of experimental group mice were significantly higher than control groups, and CD8+PD-1+ cells were significantly lower than those in MPNs + Los group and Los + laser group. And the expression of PD-1 and α-SMA in Neuro-2a tumors tissue was reduced. Furthermore, losartan could reduce damage of liver function caused by MPNs and laser treatment. This study demonstrated that losartan-induced fibroblasts ablation increased the penetration of MPNs into tumors. Enhanced penetration allowed PTT to kill more tumor cells and synergistically activate immune cells, leading to ICD, indicating the great promise of the strategy for treating neuroblastoma in vivo.