Engineering Hypoxia-Lactate-Ca Coupling for Metabolic-Ion Intervention in Cancer Immunotherapy

Lactate-rich and hypoxic tumor microenvironments (TMEs) impose a major barrier to cancer immunotherapy by sustaining metabolic immunosuppression. Although blockade of lactate export can reduce extracellular lactate burden, hypoxia-driven glycolysis continuously replenishes lactate, limiting the benefit of efflux inhibition alone. More importantly, lactate export blockade traps lactate inside tumor cells, creating an intracellular metabolic state that increases susceptibility to Ca²⁺-associated stress. Herein, we report a TME-activated nanoreactor (CZCH) that exploits this lactate trapping effect to amplify Ca²⁺-mediated immunogenic stress for tumor immunomodulation. Upon acidic activation after tumor-cell internalization, CZCH simultaneously alleviates hypoxia, blocks lactate efflux, and releases Ca²⁺, thereby coupling intracellular lactate trapping with ionic stress amplification. This mechanism is further reinforced by Ca²⁺-derived oxidative stress, which together drives severe mitochondrial dysfunction and immunogenic cell death. As a result, CZCH reshapes the immunosuppressive TME by promoting dendritic cell maturation and repolarizing macrophages toward an M1-like phenotype. In vivo, CZCH suppresses primary tumor growth, reduces pulmonary metastasis, and enhances the responsiveness of distant tumors to αPD-L1 blockade through systemic antitumor immune activation. These findings establish lactate trapping-enabled Ca²⁺ sensitization as a therapeutically actionable mechanism and provide a nanomaterial strategy for metabolic-ion intervention in cancer immunotherapy.