Abstract

Recurrence and metastasis are the leading causes of mortality in renal cell carcinoma (RCC), and its intrinsic drug resistance further limits effective therapeutic options. Synergistic activation of multiple regulated cell death pathways has recently emerged as a novel approach to overcome therapeutic resistance. Here, we developed two mitochondria-targeted iridium(III) photosensitizers, Ir-MT1 and Ir-MT2, for synergistic photoimmunotherapy of RCC. Upon white-light irradiation, Ir-MT1/2 induced severe mitochondrial damage and dysfunction, leading to massive release of mitochondrial contents. Mitochondrial DNA leakage activated the cGAS–stimulator of interferon genes pathway and caspase-1-mediated pyroptosis cascade, whereas excessive Ca 2+ efflux promoted RIPK1/RIPK3 phosphorylation and induced necroptosis. These death signals facilitated pore formation by gasdermin D and mixed lineage kinase domain-like protein in the plasma membrane, resulting in membrane rupture, release of damage-associated molecular patterns, and immunogenic cell death synergistically. In vivo, Ir-MT1/2 not only effectively suppressed primary tumor growth but also eliminated distant tumors through activation of anti-tumor immunity, exhibiting potent therapeutic efficacy and favorable biosafety. Overall, our work provides the evidence that a single iridium complex can simultaneously trigger pyroptosis–necroptosis synergy, overcoming intrinsic drug resistance and offering a promising strategy for multi-network systemic therapy of RCC.