Iridium(III) Photosensitizers Induce Simultaneous Pyroptosis and Ferroptosis for Multi‐Network Synergistic Tumor Immunotherapy

Abstract 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.