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

Abstract

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 MnO_xChP, 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 O₂ into H₂O₂, 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 Mn²⁺. Additionally, the multiple enzyme-like activities of MnO_x 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 MnO_xChP 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.