The clinical translation of photodynamic therapy (PDT) faces dual challenges of tumor hypoxia and antioxidant defense mechanisms. To address these limitations, herein tumor microenvironment (TME)-adaptive nanoparticles are rationally designed that enable oxygen-independent PDT while reprogramming immunosuppressive TME. An Ir(III) complex (Ir1) is engineered to achieve copper-mediated and glutathione (GSH)-activated switching of photodynamic modes from oxygen-dependent Type II to hypoxia-tolerant Type I PDT via coordination-induced modulation of electron transfer. This dynamic photosensitizer is precisely integrated into folate receptor-targeted azomidazole-bridged Cu(II)-MOFs, creating an "AND logic" responsive nanoplatform (Ir1@FA@MOFs) that simultaneously depletes GSH and generates hydroxyl radicals (•OH) and superoxide anion (O) under light irradiation. Mechanistic studies reveal that Ir1@FA@MOFs orchestrate multimodal cell death induction including cuproptosis, ferroptosis, and PANoptosis through mitochondrial damage. In 4T1 tumor-bearing mice, Ir1@FA@MOFs demonstrate high tumor growth inhibition while converting "cold" tumors to immunogenic hotspots. The work pioneers a TME-responsive photodynamic modality switching strategy that overcomes traditional PDT limitations through metal-coordination and GSH-activating immunogenic death programming, offering new dimensions for precision photo-immunotherapy. 2 •‒
