MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Anti-Infective Drug Development, IGCME, GBRCE for Functional Molecular Engineering, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510006, P. R. China.
State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, China.
Angew Chem Int Ed Engl. 2024 Dec 2;63(49):e202410803. doi: 10.1002/anie.202410803. Epub 2024 Oct 21.
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.
细胞焦亡与铁死亡的融合诱导细胞死亡增强免疫激活，为抗肿瘤治疗提供了一个很有前途的途径，但目前这方面的研究还很缺乏。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，并诱导光驱动的 DNA 和 Kelch 样 ECH 相关蛋白 1（KEAP1）级联损伤。受损 DNA 触发的无黑色素瘤 2（AIM2）相关细胞质核酸感应途径的激活，导致天冬氨酸半胱氨酸酶 1（caspase-1）介导的细胞焦亡。同时，铁稳态受 KEAP1/核因子红细胞 2 相关因子 2（NRF2）/血红素加氧酶 1（HO-1）通路调控，是一个关键的桥梁，不仅促进了天冬氨酸半胱氨酸酶 4（caspase-11）介导的非典型细胞焦亡，还与谷胱甘肽过氧化物酶 4（GPX4）耗竭协同诱导铁死亡。细胞焦亡和铁死亡的协同作用产生了协同效应，引发免疫原性细胞死亡，刺激强烈的免疫反应，并有效地抑制体内肿瘤生长。我们的工作引入了首个基于金属的细胞焦亡和铁死亡双重诱导剂，用于有效的癌症免疫治疗，并强调了铁稳态作为连接细胞焦亡和铁死亡协同作用的重要枢纽的意义。
