Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma

Shiqun Wang, Wei Yan, Lingkai Kong, Shuguang Zuo, Jingyi Wu, Chunxiao Zhu, Huaping Huang, Bohao He, Jie Dong () and Jiwu Wei ()
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Shiqun Wang: Medical School of Nanjing University
Wei Yan: Zhejiang University, Hang Zhou
Lingkai Kong: Medical School of Nanjing University
Shuguang Zuo: Affiliated Liutie Central Hospital of Guangxi Medical University
Jingyi Wu: Medical School of Nanjing University
Chunxiao Zhu: Chinese Academy of Sciences
Huaping Huang: Zhejiang University, Hang Zhou
Bohao He: Medical School of Nanjing University
Jie Dong: Medical School of Nanjing University
Jiwu Wei: Medical School of Nanjing University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.

Date: 2023
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DOI: 10.1038/s41467-023-39683-z

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