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Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Abstract

Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-derived metabolites play complex roles in supporting cancer progression and suppressing immune responses. Preclinical and clinical studies have shown that manipulating cholesterol metabolism inhibits tumour growth, reshapes the immunological landscape and reinvigorates anti-tumour immunity. Here, we review cholesterol metabolism in cancer cells, its role in cancer progression and the mechanisms through which cholesterol metabolites affect immune cells in the tumour microenvironment. We also discuss therapeutic strategies aimed at interfering with cholesterol metabolism, and how the combination of such approaches with existing anti-cancer therapies can have synergistic effects, thus offering new therapeutic opportunities.

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Fig. 1: Hallmarks and key drivers of cholesterol metabolism in the TME.
Fig. 2: Immune-modulation functions of cancer-derived oxysterols.

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Acknowledgements

We thank T. Horng at ShanghaiTech University for language editing, and X. He and L. Mu for figure design. C.X. is funded by CAS grants (Strategic Priority Research Program XDB29000000, Facility based Open Research Program QYZDB-SSW-SMC048, Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation), NSFC grants (31861133009, 31621003), a MOST grant (2018YFA0800700) and the Ten Thousand Talent Program “Leading talent” of China.

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C. X. designed the framework. B.-L.S. wrote the first section, and B.H. wrote the rest of the manuscript. C.X. revised the manuscript.

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Correspondence to Chenqi Xu.

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C.X. is a scientific co-founder of Hangzhou MetMed Therapeutics. The other authors declare no competing interests.

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Peer review information Primary Handling Editor: Christoph Schmitt.

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Huang, B., Song, Bl. & Xu, C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab 2, 132–141 (2020). https://doi.org/10.1038/s42255-020-0174-0

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