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

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.