整合焦亡和铁死亡混合细胞死亡诱导来增强免疫激活代表了抗肿瘤治疗的一个有前途的途径，但缺乏研究。在此，我们开发了两种铱（III）-三苯胺光敏剂 IrC 和 IrF，它们能够破坏氧化还原平衡并诱导对 DNA 和 Kelch 样 ECH 相关蛋白 1 (KEAP1) 的光驱动级联损伤。由受损 DNA 触发的黑色素瘤缺失 2 (AIM2) 相关细胞质核酸传感通路的激活，导致 Gasdermin D (GSDMD) 介导的细胞焦亡的诱导。同时，由 KEAP1/核因子红细胞 2 相关因子 2 (NRF2)/血红素加氧酶 1 (HO-1) 通路调节的铁稳态作为关键桥梁，不仅促进 Gasdermin E (GSDME) 的诱导介导的非典型焦亡，但也与谷胱甘肽过氧化物酶 4 (GPX4) 耗竭协同作用的铁死亡。焦亡和铁死亡的协同作用产生协同效应，引发免疫原性细胞死亡，刺激强大的免疫反应并有效抑制体内肿瘤生长。我们的工作介绍了第一个基于金属的小分子焦亡和铁死亡双诱导剂，用于有效的癌症免疫治疗，并强调了铁稳态作为连接焦亡和铁死亡协同效应的重要枢纽的重要性。© 2024 Wiley‐VCH GmbH。

The integration of pyroptosis and ferroptosis hybrid cell death induction to augment immune activation represents a promising avenue for anti-tumor treatment, but there is a lack of research. Herein, we developed two iridium(III)-triphenylamine photosensitizers, IrC and IrF, with the capacity to disrupt redox balance and induce photo-driven cascade damage to DNA and Kelch-like ECH-associated protein 1 (KEAP1). The activation of the absent in melanoma 2 (AIM2)-related cytoplasmic nucleic acid-sensing pathway, triggered by damaged DNA, leads to the induction of gasdermin D (GSDMD)-mediated pyroptosis. Simultaneously, iron homeostasis, regulated by the KEAP1/nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) pathway, serves as a pivotal bridge, facilitating not only the induction of gasdermin E (GSDME)-mediated non-canonical pyroptosis, but also ferroptosis in synergy with glutathione peroxidase 4 (GPX4) depletion. The collaborative action of pyroptosis and ferroptosis generates a synergistic effect that elicits immunogenic cell death, stimulates a robust immune response and effectively inhibits tumor growth in vivo. Our work introduces the first metal-based small molecule dual-inducers of pyroptosis and ferroptosis for potent cancer immunotherapy, and highlights the significance of iron homeostasis as a vital hub connecting synergistic effects of pyroptosis and ferroptosis.© 2024 Wiley‐VCH GmbH.