Abstract 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 2 •‒ ) 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.
Wang et al. (2025) studied this question.