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

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

  • Biomaterials. 2025 Oct 1:327:123760. doi: 10.1016/j.biomaterials.2025.123760.
Shijian Liu 1,  Sijie Shao 2,  Zhe Huang 3,  Panpan Xue 2,  Shuangqian Yan 4,  Mengru Cao 5,  Xuemei Zeng 6
Affiliations

Affiliations

  • 1 Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China; Department of Nephrology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
  • 2 Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE), Fuzhou, 350117, China.
  • 3 Fuzhou First General Hospital Affiliated with Fujian Medical University, Fuzhou, 350117, China.
  • 4 Strait Institute of Flexible Electronics (SIFE, Future Technologies), Fujian Key Laboratory of Flexible Electronics, Fujian Normal University and Strait Laboratory of Flexible Electronics (SLoFE), Fuzhou, 350117, China. Electronic address: ifeshqyan@fjnu.edu.cn.
  • 5 The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China. Electronic address: mengru527@hotmail.com.
  • 6 Key Laboratory of Microbial Pathogenesis and Interventions of Fujian Province University, Key Laboratory of Innate Immune Biology of Fujian Province, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, 1 Keji Road, Fuzhou, 350117, China. Electronic address: xmzeng@fjnu.edu.cn.
PMID: 41045760 DOI: 10.1016/j.biomaterials.2025.123760
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 MnOxChP, 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 MnOx 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 MnOxChP 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.

Keywords

Cancer immunotherapy; Cholesterol depletion; DNA damage repair; cGAS-STING activation.

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