JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
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2025
·
IF 2.5
Yu Pan,Rui Li,Huanhuan Ma,Xiaolei Hu,Jun Zhao,Juanjuan Qiao,Xiyao Dou,Yanan Wang,Yanzhi Zhang,Xiuli Wang,Lin Wang
Expression of the critical pyroptosis protein gasdermin E (GSDME) has been reported to be regulated by DNA methylation and negatively correlated with expression of estrogen receptor (ER) in breast cancer tissues, suggesting that estrogen-induced target gene methylation may be involved in the regulation of GSDME expression in breast cancer cells. To test this hypothesis, we treated MCF-7 and T47D ER-positive breast cancer cells with 17-β-estradiol (E 2 ), either alone or in combination with selective ERα antagonist AZD9496, selective ERβ antagonist PHTPP, DNA methyltransferase (DNMT) inhibitor RG108, and selective ER degrader Fulvestrant (Ful). Then, GSDME protein and mRNA expression were examined with western blot and RT-qPCR. Pyroptosis was induced by short-wave ultraviolet (UV-C) and detected with morphological observation, lactate dehydrogenase (LDH) release assay, and propidium iodide-Annexin V-FITC fluorescence staining. The methylation status of the GSDME promoter was tested with methylation-specific PCR. The results demonstrated that 100 nM E 2 significantly decreased GSDME protein and mRNA expression in MCF-7 and T47D cells, and significantly inhibited UV-C-induced pyroptosis. AZD9496 but not PHTPP significantly attenuated the down-regulatory effect of E 2 on GSDME expression. E 2 induced DNA methylation in the GSDME promoter region and up-regulated DNMT1 expression. RG108 strengthened UV-C-induced pyroptosis, and Ful reversed the inhibitory effects of E 2 on UV-C-induced pyroptosis of MCF-7 and T47D cells . Taken together, our study suggests that E 2 down-regulated GSDME expression in ERα-positive breast cancer by promoting GSDME promoter methylation, and inhibited UV-C-induced pyroptosis.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Pengfei Yang,Jie Zhang,Guanglei Ma,Songsong Zhi,Yi Chang,Lina Ding,Xiaoming Ma,Yuming Guo
Immunotherapy is a promising treatment strategy for tumors; however, its efficacy is limited by the complicated immunosuppressive tumor microenvironment (TME). Herein, we developed a simple drug-free bioactive multifunctional nanoplatform (named MnO 2 –CaS) that was sustainably degraded in a weakly acidic TME to release calcium ions (Ca 2+ ) and generate manganese ions (Mn 2+ ) and hydrogen sulfide (H 2 S). Mn 2+ activated and amplified the cyclic GMP-AMP (cGAMP) synthase stimulator of interferon gene (cGAS–STING) pathway and simultaneously produced oxygen to alleviate hypoxia. H 2 S, a therapeutic gas, not only induced mitochondrial damage but also prevented the extracellular efflux of Ca 2+ , leading to a sharp increase in Ca 2+ concentration in mitochondria. The abnormal intracellular Ca 2+ overload induced pyroptosis, disturbed mitochondrial respiration, and reduced metabolic oxygen consumption, thereby alleviating hypoxia and amplifying oxidative stress. Gasdermin-mediated pyroptosis facilitated mitochondrial DNA (mtDNA) release, further amplifying cGAS–STING pathway activation to induce robust antitumor immunity. In addition, the nanoplatform generated abundant reactive oxygen species (ROS) and depleted glutathione (GSH), inhibiting glutathione peroxidase 4 (GPX4) biosynthesis. This process exacerbated lipid peroxidation and induced ferroptosis. Altogether, the self-cascading immunomodulatory nanoplatform alleviated tumor hypoxia to mitigate immunosuppression and amplify pyroptosis-driven cGAS-STING pathway activation. The nanoplatform synergized with chemodynamic therapy (CDT) and ferroptosis to effectively suppress the growth and metastasis of both primary and distant tumors. This study provides a novel strategy for co-activating pyroptosis and cGAS–STING signaling in immunotherapy, offering insights for developing safe and effective immunotherapies for cancer treatment.
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CELLULAR SIGNALLING
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2023
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IF 4.8
Zeyu Xing,Mingyang Du,Yanhua Zhen,Jie Chen,Dongdong Li,Ruyin Liu,Jiahe Zheng
Atherosclerosis (AS), a metabolic disorder , is usually caused by chronic inflammation. LETM1 Domain-Containing Protein 1 (LETMD1) is a mitochondrial outer membrane protein required for mitochondrial structure. This study aims to evaluate the functional role of LETMD1 in endothelial pathogenesis of AS. Oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs) and high-fat diet apolipoprotein E -deficient (ApoE −/− ) mice were used to establish in vitro and in vivo models, respectively. Recombinant adenovirus vectors were constructed to investigate the role of LETMD1 in AS. mRNA sequencing was used to explore the effect of LETMD1 overexpression on gene expression in ox-LDL-induced HUVECs. A dual-luciferase reporting assay and chromatin immunoprecipitation (ChIP)-PCR were further conducted to verify the relationship between KLF4 and LETMD1. Results showed that LETMD1 was highly expressed in the aortas of atherosclerotic animals. LETMD1 overexpression reduced the expression of inflammatory factors, pyroptosis , ROS production, and NF-κB activation in ox-LDL-induced HUVECs, whereas LETMD1 knockdown had the opposite impact. LETMD1 overexpression was involved in regulating gene expression in ox-LDL-induced HUVECs. Overexpression of LETMD1 in mice reduced serum lipid levels as well as atherosclerotic lesions in the aortic roots. Furthermore, LETMD1 overexpression suppressed inflammatory reactions, cell pyroptosis, nuclear p65 protein level, cell apoptosis, and ROS generation in the aortas of AS mice. KLF4 (Krüppel-like factor 4) was found to be the transcriptional regulator of LETMD1. In conclusion, LETMD1, a target of KLF4, hinders endothelial inflammation and pyroptosis, which is a mechanism inhibiting the development of atherosclerosis.
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Antioxidants
·
2026
·Vol. 15
·期 10
·1284
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IF 8.2
Xingyao Pei,Zibin Li,Chun Chen,Wenjuan Zhang,Shang Wang,Yuefei Sun,Chongshan Dai,Daowen Li
Zinc oxide nanoparticles (ZnO NPs) have been applied in biomedicine, food processing, and agricultural production. ZnO NPs can cause potential hepatotoxicity in animals and humans; however, the precise molecular mechanisms remain unclear and the effective treatment strategies are scarce. In this study, we investigated the protective effects of paeoniflorin (PF), a bioactive compound extracted from the roots of Paeoniaceae plants, on ZnO NPs-induced hepatotoxicity using a cell model. Our results showed that PF supplementation can dose-dependently attenuate ZnO NPs-induced decreases in cell viability and oxidative damage in HepG2 cells. Mechanistically, PF significantly reduced the activation of NLRP3 inflammasome, then reduced the expression of GSDMD-NT cleavage and the secretion of IL-1β and IL-18, and finally ameliorated ZnO NPs-induced pyroptosis. Furthermore, PF can directly interact with SIRT1, then deacetylate TFEB and promote autophagy-lysosome biogenesis. Overexpression of TFEB markedly attenuated ZnO NPs-induced pyroptosis. Consistently, the inhibition of SIRT1 or knockdown of TFEB both partly attenuated the protective effect of PF. Taken together, for the first time, our study demonstrated that PF can directly target SIRT1, then effectively attenuate ZnO NPs-induced pyroptosis via the activation the SIRT1/TFEB signaling pathway.
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Frontiers in Immunology
·
2025
·
IF 5.9
You Zhou,Kai Yang,Jian Wang,Ruijuan Guan,Wei Liu,Chaowei Wen,Liang Yuan,Tiange Zhang,Wei Feng,Yuanyuan Li,Jingyi Xu,Wenju Lu
Backgrounds: Exposure to fine particulate matter (PM2.5) triggers airway inflammation through the activation of the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway, contributing to the pathogenesis of various acute and chronic respiratory diseases. Mucin 1 (MUC1), a transmembrane glycoprotein highly expressed on airway epithelial cells, is known to modulate TLR-mediated inflammatory responses. However, the specific role and molecular mechanism by which MUC1 regulates PM2.5-induced airway inflammation remain inadequately understood.Methods: Lung injury models were established using Muc1+/+ and Muc1-/- rats via intranasal instillation of PM2.5. Histopathological changes and inflammatory responses were evaluated following treatment. In parallel, human bronchial epithelial cells (16HBE) were transfected with MUC1 overexpression and knockdown plasmids, along with corresponding controls. An IRAK4-specific inhibitor was employed to explore the mechanistic role of MUC1 in regulating the TLR4/IRAK4/NF-κB signaling cascade and associated pyroptosis.Results: PM2.5 exposure caused notable epithelial disruption, inflammatory infiltration, and submucosal fibrosis in Muc1-/- rats compared to Muc1+/+ controls. While TLR4 expression was not significantly altered, NF-κB and NLRP3 inflammasome activity were markedly elevated in Muc1-deficient rats. In 16HBE cells, MUC1 overexpression attenuated, whereas MUC1 knockdown exacerbated, PM2.5-induced activation of the IRAK4/NF-κB signaling axis and pyroptosis-related markers (IL-1β, IL-18, NLRP3, GSDMD). Furthermore, pharmacological inhibition of IRAK4 mitigated these effects, confirming the involvement of the IRAK4 pathway in MUC1-mediated protection.Conclusions: MUC1 is upregulated in airway epithelial cells upon PM2.5 exposure and serves as a key endogenous inhibitor of airway inflammation. It exerts its anti-inflammatory and anti-pyroptotic effects by suppressing IRAK4 phosphorylation, thereby modulating downstream NF-κB/NLRP3/GSDMD signaling. These findings highlight MUC1 as a potential therapeutic target for PM2.5-induced airway inflammatory diseases.
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CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Gao He,Ziyu Feng,Xinghai Liu,Muyu Zhu,Xiaoan Liu,Lile Dong,Xiafei Yu
HB@T nanosheets generate sustained ROS under ultrasound activation, inducing redox collapse and mitochondrial damage. • ROS-mediated mitochondrial injury activates the canonical NLRP3/caspase-1/GSDMD pathway and triggers pyroptotic cell death. • HB@T-induced pyroptosis promotes CRT release, DC maturation, and systemic antitumor immunity with abscopal effects. Triple-negative breast cancer (TNBC) remains one of the most treatment-refractory malignancies, largely attributable to its profoundly immunosuppressive microenvironment that enables tumor immune evasion. Pyroptosis, a gasdermin-mediated lytic cell death pathway, holds promise for reinvigorating antitumor immunity through the release of immunostimulatory signals. However, the clinical translation of pyroptosis-based therapy is hindered by the lack of spatiotemporally controllable triggers and the robust glutathione (GSH)-centered antioxidant defense inherent to TNBC cells. Herein, a defect-engineered core-shell Bi 4 TaO 8 Br@TaO X (HB@T) piezoelectric nanosheet is developed as an ultrasound (US)-responsive platform to circumvent these barriers. Structurally, HB@T comprises a crystalline Bi₄TaO₈Br core that ensures stable charge generation, surrounded by an oxygen-vacancy-rich amorphous Ta-based oxide shell that facilitates oxygen pre-adsorption and GSH consumption. This rational design yields a narrowed bandgap of 2.36 eV and an elevated piezoelectric coefficient (d33 = 24.1 pm V −1 ), enabling efficient electron-hole separation and robust reactive oxygen species (ROS) production under US stimulation. The dual functionality of sustained ROS generation coupled with active GSH depletion synergistically disrupts redox homeostasis in tumor cells, thereby triggering the NLRP3/caspase-1/GSDMD pyroptotic cascade. This process elicits profound immunogenic responses, including dendritic cell maturation, CD8 + T cell infiltration, and expansion of effector memory (T EM ) and central memory (T CM ) T cell populations. Remarkably, in a bilateral tumor model, HB@T treatment achieves 71% inhibition of primary tumors and 67% suppression of distant untreated lesions, demonstrating a potent abscopal effect indicative of systemic immune reactivation. Collectively, this work establishes an innovative therapeutic paradigm that integrates US-activated piezoelectric catalysis with pyroptosis-driven immunomodulation, offering a clinically translatable strategy to overcome immune tolerance in TNBC. Defect-engineered core-shell HB@T piezoelectric nanosheet is developed as an US-responsive platform to induce pyroptosis and elicit systemic abscopal antitumor immunity. The dual functionality of ROS generation coupled with GSH depletion synergistically disrupts redox homeostasis, triggering the NLRP3/caspase-1/GSDMD pyroptotic cascade. Remarkably, HB@T treatment achieves 71% inhibition of primary tumors and 67% suppression of distant untreated lesions, demonstrating a potent abscopal effect indicative of systemic immune reactivation. Download: Download high-res image (128KB) Download: Download full-size image
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
·
IF 15
Liu Lin,Huang Kaiyan,Guo Hanjing,He Linping,Wang Xin,Wang Chao,Lin Jianqing,Huang Naihan,Miao Weibing
Internal radiation therapy is an irreplaceable modality for local tumor treatment, offering high-effective radiotherapy while sparing surrounding healthy tissues. However, current clinical non-biodegradable radionuclide implants suffer from permanent retention risks and limited efficacy against distal tumors due to inadequate immune activation. Herein, we engineered a biodegradable radionuclide-labeled oxygen-self-supplying calcium reservoir ( 131 I@CaO 2 ), fabricated through biomimetic mineralization followed by chloramine-T mediated 131 I-radiolabeling, for high-efficiency internal-radioimmunotherapy. 131 I@CaO 2 effectively enhances the internalization of 131 I to improve internal-radiotherapy and exhibits pH-responsive biodegradability, remaining stable under physiological condition while progressively degrading in tumor microenvironment to release H 2 O 2 , O 2 and Ca 2+ . These bioactivators synergistically enhance 131 I-induced internal-radioimmunotherapy through both radiosensitization and immune activation: H 2 O 2 and O 2 boost 131 I-induced ROS generation while Ca 2+ disrupted mitochondrial respiration to reduce oxygen consumption and ATP production (suppressing Ca 2+ pump activity), creating a positive feedback loop of oxygen supply and ion overload, thereby achieving radiosensitization; Concurrently, O 2 alleviates tumor hypoxia to downregulate PD-L1 expression and Ca 2+ overload activates dual pyroptosis pathways, establishing a robust immunogenic microenvironment. As a result, 131 I@CaO 2 effectively eliminates both primary and distant tumors by activating immune cells. This study simultaneously resolves the long-term retention risks of non-biodegradable radionuclide and the dichotomy between local radiotherapy and comprehensive immune modulation.
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Wenjia Liu,Ying Wang,Xiangyu Hao,Yangxun Wang,Xiaofan Zhang,Jinchao Zhang,Kun Ge,Guoqiang Zhou
Triple-negative breast cancer (TNBC) is associated with rapid progression and poor sensitivity to monotherapies, necessitating combination strategies to enhance tumor immunogenicity, reprogram the tumor microenvironment (TME), and convert immunologically "cold" tumors into "hot" ones. In this study, we develop a pH-responsive, pyroptosis-inducing nanoreactor, ZnS/ZIF-90:Fe/Vk3 (ZZFV), designed to elicit potent antitumor immunity. Under acidic conditions, ZZFV rapidly degrades, releasing Zn 2+ , Fe 2+ , H 2 S, and Vk3. H 2 S promotes glucose uptake and consumption while downregulating cytochrome c oxidase subunit IV (COX IV) expression, whereas Zn 2+ suppresses lactate dehydrogenase (LDH) activity, collectively disrupting glucose metabolism and exacerbating intracellular acidification. Meanwhile, NAD(P)H quinone oxidoreductase 1 (NQO1), highly expressed in tumor cells, catalyzes the conversion of Vk3 to H 2 O 2 , which is subsequently converted to highly toxic •OH through Fe 2+ -mediated Fenton reactions. Additionally, Zn 2+ and H 2 S synergistically disrupt mitochondrial function, thereby amplifying reactive oxygen species (ROS) production. Excessive ROS triggers Caspase-1-dependent pyroptosis, leading to the liberation of damage-associated molecular patterns. These events promote dendritic cell (DC) maturation, robust T-cell activation, M1 macrophage polarization, and expansion of central memory T-cell populations, thereby conferring durable immune protection. Consequently, ZZFV demonstrates potent antitumor efficacy, effectively overcoming immune tolerance in TNBC and achieving robust, sustained antitumor immunity.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
·
IF 6.1
Huan Zeng,Jingyi Qi,Qiyi Chen,Ruowei Zhang,Chen Guo,Jinghua Zhao,Huimei Liang,Junlong Sun,Wei Wang,Houhui Song
Nanoplastics (NPs), highly prevalent due to large-scale plastic production, and glyphosate (Gly), the most utilized herbicides worldwide, are ubiquitous environmental contaminants. Growing concerns highlight that NPs can act as vectors for various pollutants like Gly, but their combined toxic effects in mammals and the underlying mechanisms remain poorly understood. In this study, the hepatotoxicity and potential mechanisms under the exposure of polystyrene nanoplastics (PSNPs) and/or Gly in vivo and in vitro were investigated. Mice were treated with PSNPs (25 mg/kg/day) and/or Gly (50 mg/kg/day) by oral gavage for 5 weeks. Results showed that exposure to PSNPs or Gly caused liver injury in mice, with co-exposure resulting exacerbated hepatotoxicity, evidenced by increased neutrophil infiltration and ultrastructural damages, elevated oxidative stress (LPO, H 2 O 2 , T-AOC and CAT), increased neutrophil chemokines (CCL2, CXCL12) and marker of neutrophil extracellular traps (NETs) formation (MPO), and upregulated pyroptosis-related factors (TLR4, NF-κB, NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18). In addition, a co-culture system of peripheral blood neutrophils (PBNs) and AML12 cells was established, revealing that co-exposure amplified ROS production, NETs formation (SYTOX Green staining) and pyroptosis. Notably, inhibition of the NLRP3 inflammasome significantly reduced NETs production, and degradation of NETs substantially decreased pyroptosis, demonstrating feedback between NETs and the NLRP3 inflammasome that drives inflammation induced by PSNPs and Gly. These results highlight that co-exposure exacerbated NETs-mediated pyroptosis through NLRP3 inflammasome activation. Our study equips new reference for understanding the mechanistic insights and health implications of the combined toxicity of PSNPs and Gly.
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INTERNATIONAL JOURNAL OF HYPERTHERMIA
·
2024
·
IF 3
Guanghui Zi,Jin Chen,Yatu Peng,Yue Wang,Baowei Peng
Background Hyperthermia can play a synergistic role with chemotherapy in combination therapy. Although the association between caspase activation, apoptosis, and pyroptosis have been published for both cisplatin (CDDP) and hyperthermia therapies independently, the interactions between these molecular pathways in combination therapy are unknown. The present study aimed to investigate the possible interactions between caspase 8 activation, apoptosis, and pyroptosis in combination therapy.Methods Cells were treated with CDDP (15 µg/ml), followed by hyperthermia at optimized temperature (42.5 °C) in water-bath. After combination therapy, cell viability was analyzed by CCK-8, and cell death was analyzed by Annexin-V-FITC/PI and caspases activation. Immuno-staining and co-immuno-precipitation were used to examine the interaction between p62 and caspase-8. Pyroptosis was investigated by western blotting and transmission electron microscopy. E3 ligase Cullin 3 was knockdown by siRNA. In addition, caspase-8 activation was modulated by CRISPR-Cas9 gene-editing or pharmacological inhibition.Results Combination therapy promoted K63-linked polyubiquitination of caspase-8 and cellular accumulation of caspase-8. In turn, polyubiquitinated caspase-8 interacted with p62 and led to the activation of caspase-3. Knockdown of the E3 ligase Cullin 3 by siRNA reduced caspase-8 polyubiquitination and activation. In addition, combination therapy induced release of the pore-forming N-terminus from gasdermins and promoted pyroptosis along with caspase-8 accumulation and activation. Knockdown of caspase-8 by CRISPR/Cas9 based gene editing reduced the sensitivity of tumor cells to apoptosis and pyroptosis.Conclusions Our study presented a novel mechanism in which hyperthermia synergized with chemotherapy in promoting apoptosis and pyroptosis in a caspase-8 dependent manner.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Shousheng Liu,Haiping Zhang,Ronghuan Du,Xi Gao,Tianren Wang,Wenping Qin,Dan Sun,Hui Liang,Peng Wang
Emerging research evidence has established the critical role of inflammatory cascades in the development and progression of alcoholic liver injury with hepatocellular death serving as a principal driver. Notably, the dysregulated interplay between mitochondrial homeostasis and pyroptosis is primarily responsible for the alcohol-induced aberrant liver immune microenvironment, characterized by nonresolving inflammation. Given the considerable limitations in the current treatment for alcoholic steatohepatitis (ASH), it is imperative to explore targeted nutritional interventions as alternative therapies. Here, we established an ASH model with C57BL/6J mice and demonstrated that astaxanthin (AST) administration significantly protected against alcohol-induced inflammatory liver injury through dual mechanisms: 1) suppression of hepatocyte pyroptosis by inhibiting the NLRP-3/Caspase/GSDMD signaling axis and 2) mitigation of mitochondrial dysfunction evidenced by structural membrane integrity restoration and redox homeostasis rebalancing. Mechanistically, AST intervention impeded the cytoplasmic translocation of mitochondrial DNA (mtDNA), thereby concurrently inhibiting AIM2 inflammasome activation and cGAS/STING signaling. In vitro studies further confirmed dose-dependent attenuation of alcohol-induced hepatotoxicity by AST, marked by reduced pyroptotic cell death and diminished proinflammatory cytokine secretion (IL-1β, IL-18). Mitochondrial protection was further evidenced through restored membrane potential (ΔΨm), decreased cytoplasmic Cytochrome C release, and attenuated mtDNA leakage. Moreover, we identified a novel molecular interaction, wherein AST competitively binds lipid-binding motifs within the β1−β2 loop of the GSDMD-N-terminal domain, potentially interfering with pyroptotic pore formation. Further overexpression experiments confirmed the improvement effect of AST on pyroptosis induced by GSDMD-N pore formation. Concurrently, AST exhibited potent antioxidant effects against alcohol-induced cardiolipin peroxidation, suggesting dual therapeutic modalities targeting both pyroptotic execution and mitochondrial membrane stabilization. Collectively, our findings identify AST as a promising candidate for therapeutic interventions against alcoholic inflammatory liver injury through coordinated modulation of the pyroptosis-mitochondrial homeostasis crosstalk, offering novel insights into nutritional intervention strategies for alcohol-related liver pathologies.
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BIOMATERIALS
·
2026
·
IF 13.6
Changhao Dong,Ju Huang,Lanlan You,Lan Chen,Minglan Wang,Jun Zheng,Heyang Liu,Lin Li,Pan Li,Zhigang Wang,Han Lin,Liang Zhang
Zinc ions (Zn 2+ ) overload is considered an exceptionally safe and ideal approach for pyroptosis-mediated tumor treatment. However, achieving efficient and safe induction of tumor-specific Zn 2+ overload remains a significant challenge. This study pioneers the concept of “sono-activated Zn 2+ storm”, developing a sono-activated and tumor microenvironment (TME)-responsive nanoplatform, Zn-TCPP@CaCO 3 , which enables a precise and spatiotemporally controllable induction of Zn 2+ overload at the tumor site. Specifically, Zn-TCPP@CaCO 3 selectively releases meso-tetra-(4-carboxyphenyl) porphine (TCPP) and delivers the “exogenous Zn 2+ ” within the acidic TME. Upon tumor-site localized ultrasound irradiation, the sonosensitizer TCPP generates abundant reactive oxygen species (ROS) in situ, which oxidatively attack Zn-metallothionein complexes and effectively unlock the “endogenous Zn 2+ ” reservoir. The synergistic influx of exogenous and endogenous Zn 2+ drastically disrupts intracellular zinc homeostasis, further exacerbating oxidative stress by impairing mitochondrial function. This disruption initiates a self-amplifying positive feedback loop, ultimately inducing a potent “Zn 2+ storm” that finally triggers tumor cell pyroptosis. The results demonstrate that this strategy not only effectively induces powerful antitumor effects, but also elicits a strong immunogenic response and significantly enhances the therapeutic efficacy of immune checkpoint inhibitors. Overall, this work provides valuable insights into the development of novel tumor specific ion interference therapies.
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