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

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.