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25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages

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机构: [1]Key Laboratory of RNA Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2]School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China [3]Department of Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China [4]State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Metabonomics and Systems Biology Laboratory at Shanghai International Centre for Molecular Phenomics, Zhongshan Hospital, Fudan University, Shanghai 200032, China [5]Shanghai Institute of Immunology, Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Hongqiao International Institute of Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China [6]State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China [7]Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, No. 150 Jimo Road, Shanghai, China [8]National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China [9]Cancer Center, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, Shanghai 200072, China [10]Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
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Macrophages are critical to turn noninflamed "cold tumors" into inflamed "hot tumors". Emerging evidence indicates abnormal cholesterol metabolites in the tumor microenvironment (TME) with unclear function. Here, we uncovered the inducible expression of cholesterol-25-hydroxylase (Ch25h) by interleukin-4 (IL-4) and interleukin-13 (IL-13) via the transcription factor STAT6, causing 25-hydroxycholesterol (25HC) accumulation. scRNA-seq analysis confirmed that CH25Hhi subsets were enriched in immunosuppressive macrophage subsets and correlated to lower survival rates in pan-cancers. Targeting CH25H abrogated macrophage immunosuppressive function to enhance infiltrating T cell numbers and activation, which synergized with anti-PD-1 to improve anti-tumor efficacy. Mechanically, lysosome-accumulated 25HC competed with cholesterol for GPR155 binding to inhibit the kinase mTORC1, leading to AMPKα activation and metabolic reprogramming. AMPKα also phosphorylated STAT6 Ser564 to enhance STAT6 activation and ARG1 production. Together, we propose CH25H as an immunometabolic checkpoint, which manipulates macrophage fate to reshape CD8+ T cell surveillance and anti-tumor response.Copyright © 2024 Elsevier Inc. All rights reserved.

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大类 | 1 区 医学
小类 | 1 区 免疫学
最新[2023]版:
大类 | 1 区 医学
小类 | 1 区 免疫学
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Q1 IMMUNOLOGY
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Q1 IMMUNOLOGY

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第一作者机构: [1]Key Laboratory of RNA Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China [3]Department of Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
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通讯机构: [1]Key Laboratory of RNA Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2]School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China [6]State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China [9]Cancer Center, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, Shanghai 200072, China [10]Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
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