Biodegradable Nano‐Regulator Reprograms Glioblastoma Immunosuppression: Pyroptosis‐Metabolism‐Immunity Crosstalk for Cascading Immune Activation

Abstract Glioblastoma's (GBM) resistance to immunotherapy is primarily attributed to its immunosuppressive tumor microenvironments (TME), characterized by metabolic dysregulation and immune desertification. To tackle these challenges, we developed an innovative immune‐activating nano‐regulator (MnCP‐LIGHT@GL) by biomineralizing with Mn 2+ , cholesterol oxidase (CHOx) and pyruvate oxidase (POx), and loading tumor necrosis factor superfamily member 14 (LIGHT) and functionalizing with glioma cell membranes for efficient immunotherapy of GBM. MnCP‐LIGHT@GL with dual enzyme activities successfully triggered reactive oxygen species (ROS)‐dependent caspase‐1‐mediated pyroptosis through Mn 2+ ‐mediated Fenton‐like reaction, which is improved by the H 2 O 2 generated from the oxidation of endogenous cholesterol and pyruvate. Concurrently, ChOx and POx disrupt cholesterol metabolism and the Warburg effect, reducing the accumulation of immunosuppressive metabolites (cholesterol and lactic acid) within TME. LIGHT drives tumor vessel normalization, induces the formation of tumor‐associated high endothelial venules (TA‐HEVs), and promotes the neogenesis of tertiary lymphoid structures (TLS). These LIGHT‐mediated structural alterations synergize with damage‐associated molecular patterns (DAMPs) released from pyroptotic cells, collectively promoting the infiltration, and activation of immune cells into the tumor site, further potentiating the anti‐tumor immune response. This study establishes a novel therapeutic paradigm against GBM immunosuppressive TME through the synergistic effect of immunogenic cell death, metabolic reprogramming, and immune amplification.