2. Academic Validation
  3. Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma

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

  • Nat Commun. 2023 Jul 20;14(1):4367. doi: 10.1038/s41467-023-39683-z.
Shiqun Wang # 1 2,  Wei Yan # 3 4,  Lingkai Kong # 1,  Shuguang Zuo 5,  Jingyi Wu 1,  Chunxiao Zhu 2 6,  Huaping Huang 3 4,  Bohao He 1,  Jie Dong 7,  Jiwu Wei 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, Jiangsu, China.
  • 2 Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
  • 3 Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hang Zhou, Zhejiang, China.
  • 4 Clinical Research Center for Neurological Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
  • 5 Liuzhou Key Laboratory of Molecular Diagnosis, Guangxi Key Laboratory of Molecular Diagnosis and Application, Affiliated Liutie Central Hospital of Guangxi Medical University, Liuzhou, Guangxi, China.
  • 6 School of Molecular Medicine, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, Zhejiang, China.
  • 7 State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, Jiangsu, China. dongjie@nju.edu.cn.
  • 8 State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing, Jiangsu, China. wjw@nju.edu.cn.
  • 9 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu, China. wjw@nju.edu.cn.
  • # Contributed equally.
PMID: 37474548 DOI: 10.1038/s41467-023-39683-z
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.

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