Hypoxia‐Adaptive Confined Cascade Nanoplatform Unleashing ROS/RNS Storm and Metal Ions to Orchestrate Necroptosis, Ferroptosis, and cGAS‐STING Immunity

The hypoxic and immunosuppressive tumor microenvironment limits photodynamic therapy (PDT) and antitumor immunity. To address this, we construct a hypoxia‐adaptive nanoplatform PG@Mn‐ZIF8 by co‐encapsulating a J‐aggregating platinum photosensitizer Pt‐3T and the nitric oxide (NO) donor S‐nitrosoglutathione (GSNO) within Mn 2+ /Zn 2+ doped ZIF‐8. This nanoplatform can decompose endogenous H 2 O 2 to O 2 via Pt aggregate‐mediated catalase (CAT)‐mimetic activity, alleviating hypoxia before light irradiation. Upon illumination, Pt‐3T generates a robust Type I/II reactive oxygen species (ROS) storm, which triggers rapid NO release from GSNO, and further convert ROS and NO into highly cytotoxic peroxynitrite (ONOO •− ), thereby amplifying an ROS/RNS storm within the confined MOF space. This co storm disrupts redox homeostasis to induce both necroptosis and ferroptosis alongside immunogenic cell death (ICD). Moreover, the released Mn 2+ and Zn 2+ upon MOF degradation synergistically potentiate the cyclic GMP‐AMP (cGAMP) synthase (cGAS)–stimulator of interferon genes (STING) pathway. Consequently, the spatiotemporal “O 2 –ROS/RNS–metal ions” cascade enables the nanoplatform to trigger multimodal cell death and ignite cGAS‐STING‐driven innate and adaptive immunity, eradicating solid tumors, establishing long‐term immune memory, and reversing the “cold” tumor phenotype.