The deficiency in immunogenicity and the presence of immunosuppression within the tumor microenvironment significantly hindered the efficacy of immunotherapy. Consequently, a nanoformulation containing metal sulfide of FeS and GSDMD plasmid (NPFeS/GD) had been developed to effectively augment antitumor immune responses through dual activation of immunogenic PANoptosis and ferroptosis, as well as reprogramming immunosuppressive effects via H2S amplification. The bioactive NPFeS/GD exhibited controlled release of GSDMD plasmid, H2S, and Fe2+ in response to the tumor microenvironment. Fe2+, H2S, and the expression of GSDMD protein could effectively elicit highly immunogenic PANoptosis and ferroptosis. Furthermore, releasing H2S could mitigate the overexpression of indoleamine 2,3-dioxygenase1 (IDO1) induced by immunogenic PANoptotic and ferroptotic cell death and disrupt the activity of IDO1. Consequently, NPFeS/GD effectively triggered the antitumor innate and adaptive immune responses through induction of PANoptotic and ferroptotic cell death and reshaped the tumor immunosuppressive microenvironment to enhance antitumor immunotherapy for metastasis inhibition. This study unveiled the significant potential of immunogenic PANoptosis and ferroptosis in H2S gas therapy for enhancing tumor immunotherapy, offering novel insights and ideas for the rational design of nanomedicine to enhance tumor immunogenicity while reprogramming the tumor immunosuppressive microenvironment.

中文翻译：

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通过 H2S 扩增纳米制剂双重激活免疫原性全细胞凋亡和铁死亡重塑肿瘤免疫抑制微环境，以增强癌症免疫治疗


免疫原性缺陷和肿瘤微环境中免疫抑制的存在显着阻碍了免疫治疗的疗效。因此，开发了一种含有 FeS 和 GSDMD 质粒金属硫化物 （NPFeS/GD） 的纳米制剂，通过免疫原性 PANoptosis 和 Ferrorculosis的双重激活，以及通过 H2S 扩增重编程免疫抑制作用，有效增强抗肿瘤免疫反应。生物活性 NPFeS/GD 响应肿瘤微环境表现出 GSDMD 质粒、 H2S 和 Fe2+ 的受控释放。Fe2+、H2S 和 GSDMD 蛋白的表达可有效引发高免疫原性 PANoptisis 和 Ferrroptosis。此外，释放 H2S 可以减轻免疫原性 PANoptotic 和 ferroptotic 细胞死亡诱导的吲哚胺 2,3-双加氧酶 1 （IDO1） 的过表达，并破坏 IDO1 的活性。因此，NPFeS/GD 通过诱导 PANoptotic 和 ferroptotic 细胞死亡有效触发抗肿瘤先天性和适应性免疫反应，并重塑肿瘤免疫抑制微环境以增强抗肿瘤免疫治疗以抑制转移。本研究揭示了 H2S 气体疗法中免疫原性 PANoptosis 和 Ferrr死亡 在增强肿瘤免疫治疗方面的巨大潜力，为合理设计纳米药物以增强肿瘤免疫原性，同时重新编程肿瘤免疫抑制微环境提供了新的见解和思路。