A multifunctional manganese-based nanozyme platform for synergistic hypoxia alleviation and cholesterol depletion to potentiate STING-mediated cancer immunotherapy.

Aberrant cholesterol accumulation and hypoxia contribute to cancer malignancy by promoting cell survival, enhancing DNA repair pathways, reducing the efficacy of the stimulator of the interferon gene (STING) activation, and creating an immunosuppressive tumor microenvironment. In this study, we developed a manganese-based nanoplatform, termed MnOChP, which combines peroxidase-, catalase-, glutathione oxidase-, and NADPH oxidase-like nanozyme activities with cholesterol oxidase (ChOx) to enhance STING activation for effective cancer immunotherapy by modulating cholesterol metabolism and hypoxia. ChOx catalyzes the oxidation of cholesterol and O into HO, depleting cholesterol, which disrupts lipid rafts domains, inhibits DNA damage repair, and increases membrane fluidity. This process amplifies the cytosolic DNA pool, induced by lethal OH from the Fenton-like reaction, thereby strengthening STING activation mediated by Mn. Additionally, the multiple enzyme-like activities of MnO overcome the tumor's antioxidant defense system and alleviate hypoxia, further enhancing OH-induced lethality and cholesterol oxidation. Cholesterol depletion also inhibits the PD-1/PD-L1 axis, mitigating CD8 T cells exhaustion. The MnOChP nanoplatform induces potent immunogenic cell death, demonstrating significant immunotherapeutic efficacy in both abscopal and metastasis mouse models. This strategy amplifies STING activation and expands the potential of cholesterol metabolism modulation-based immunotherapy.