Mitochondria‐Targeting Iridium(III) Complexes Induce PANoptosis and Ferroptosis for Boosting Chemoimmunotherapy Against Immune‐Desert Colorectal Cancer

Abstract

ABSTRACT Over 80% of colorectal cancer (CRC) cases are classified as microsatellite stable (MSS), a subtype characterized by an immunosuppressive tumor microenvironment that poses a significant challenge for chemotherapy. Emerging evidence suggests that inflammatory programmed cell death pathways can effectively activate anti‐cancer immunity across various cancer types. However, studies exploring the role of these death pathways in reversing the immune desertification and providing unique therapeutic advantages in MSS‐CRC remain scarce. Herein, we present a strategy using iridium(III)‐based inducers to concurrently trigger immunogenic PANoptosis and ferroptosis, aiming to reverse the “immune desert” phenotype of MSS‐CRC and integrate chemotherapy with immunotherapy. Upon mitochondrial accumulation, these iridium(III) compounds inhibit complex I of the electron transport chain, leading to electron leakage and excessive reactive oxygen species generation, which collectively initiate the PANoptotic and ferroptotic signaling pathways in MSS‐CRC. Proteomic analysis and in vivo experiments further demonstrated that Ir2 can activate PANoptotic and ferroptotic pathways to counteract immune desertification in MSS‐CRC. Importantly, this study establishes a mechanism‐guided chemical design strategy whereby subtle ligand engineering within a cyclometalated Ir(III) platform governs mitochondrial accumulation, redox disruption, and subsequent induction of immunogenic cell death.