Cyclometalated iridium complex with red-light activation for dual ferroptosis-apoptosis cancer therapy

Conventional cancer therapies such as chemotherapy primarily rely on apoptosis induction; however, their efficacy is often compromised by the development of apoptosis resistance in tumor cells. A new cyclometalated iridium complex, IrOAc, was designed and synthesized in this study. Its improved red-light absorption in the 650-700 nm biological window offers potential advantages for the treatment of deep-seated and hypoxic tumors. Upon irradiation, IrOAc generates reactive oxygen species (ROS) via both Type I and Type II photodynamic pathways, disrupting cellular redox homeostasis and inducing lipid peroxidation, thereby triggering both potential ferroptosis and apoptosis. In vitro studies demonstrate that IrOAc exhibits markedly enhanced cytotoxicity against RM-1 prostate cancer cells under 650 nm irradiation, along with significant inhibition of colony formation and cell migration. Mechanistic investigations reveal depletion of intracellular glutathione (GSH), downregulation of glutathione peroxidase 4 (GPX4) expression, and characteristic mitochondrial alterations associated with ferroptosis. Notably, IrOAc also promotes caspase-3 activation (cleavage), further facilitating apoptotic cell death. In vivo experiments demonstrate that IrOAc combined with red-light irradiation effectively suppresses tumor growth without inducing noticeable systemic toxicity; this therapeutic effect was accompanied by an increased proportion of splenic CD8+ T cells and elevated intratumoral IFN-γ levels, suggesting potential immunomodulatory activity. Collectively, IrOAc represents a promising red-light-responsive photodynamic agent combining chemotherapeutic and photodynamic activities, with favorable biosafety and immunomodulatory potential, offering a novel strategy to overcome tumor resistance and enable precise cancer therapy.