Self-Sustaining Catalytic-Immunological Cycle Powered by a Tumor Microenvironment-Engineered Iridium-MnO2 Nanozyme for Photodynamic Immunotherapy.

Abstract

The hypoxic and immunosuppressive tumor microenvironment limits photodynamic therapy (PDT). We designed a TME-responsive nanoplatform (Ir@MnO2@TK/FA) with MnO2 nanoshells, a perfluorocarbon (PFC)-modified iridium(III) photosensitizer (Ir-PFC), a reactive oxygen species (ROS)-responsive polymer, and a tumor-targeting folic acid ligand. MnO2 decomposes H2O2 to O2, and PFC stores O2, together alleviating hypoxia. Upon light irradiation, enhanced O2 boosts ROS generation via type I/II pathways. In vitro and in vivo studies show efficient O2 self-supply, multiple ROS production, potent cytotoxicity under hypoxia, and induction of necroptosis, pyroptosis, and immunogenic cell death. Released Mn2+ activates cGAS-STING. In vivo, the system relieves hypoxia and reverses immunosuppression. Overall, this work introduces an innovative nanoplatform that establishes a self-reinforcing cycle of hypoxia alleviation and immune activation, offering a potent combinatorial strategy to surmount PDT resistance and amplify antitumor immunity.