Abstract
Cytotoxic lymphocytes use perforin to form plasma membrane (PM) pores in tumor cells, thereby enabling granzyme-mediated cell death. However, whether and how tumor metabolism enables PM repair to evade immunity is unclear. In this study, using a functional screen targeting 111 metabolic enzymes, we identified hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) as critical for repairing perforin-induced PM damage. HMGCS1 promotes PM repair by initiating de novo cholesterol synthesis, enhancing tumor cell resistance to lymphocyte-mediated killing and impairing the efficacy of NK, CAR-T, and anti-PD-1-based immunotherapies. Beyond its structural role, cholesterol directly binds charged multivesicular body protein 4b (CHMP4B) to enhance its PM localization, facilitating PM repair. Furthermore, oncogenic activation, cytokine, and hypoxia induce c-Jun activation, up-regulating HMGCS1 expression. In lung cancer patients, elevated c-Jun activation, HMGCS1 expression, cholesterol content and PM CHMP4B correlate with reduced anti-PD-1 immunotherapy efficacy. Our findings reveal a tumor immune evasion mechanism wherein HMGCS1 drives cholesterol-dependent PM repair by activating the cholesterol synthesis. Targeting HMGCS1 enhances the effectiveness of immunotherapies.
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Acknowledgements
We thank the Genome Tagging Project (GTP) Center and the Core Facilities of CEMCS for technical support. We thank Shuai Han for providing technical help at the CEMCS Core Facility.
Funding
W.Y. discloses support for the research of this work from the National Key R&D Program of China (2024YFA1306000, 2022YFA0806200), the National Natural Science Foundation of China (32521007, 92357301, 32025013). Y.Zhang. discloses support for the research of this work from the National Natural Science Foundation of China (32470821). W.Y. discloses support for the research of this work from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0990000), the Science and Technology Commission of Shanghai Municipality (24J12800600), Shanghai Municipal Science and Technology Major Project, the CAS Project for Young Scientists in Basic Research (YSBR-014), the Research Funds of Hangzhou Institute for Advanced Study, UCAS (2025HIAS-ZL014), the Foundation of Shanghai Key Laboratory of Thoracic Tumor Biotherapy (2025SZ1701), and the Shanghai Academy of Natural Sciences (SANS). Y.Zhang discloses support for the research of this work from the Shanghai Oriental Talent Program and the National Key R&D Program of China (2024YFA1306000). F.Y. discloses support for the research of this work from the National Natural Science Foundation of China (82373059). H.Yang. discloses support for the research of this work from the National Natural Science Foundation of China (82202925) and the Clinical Research Special Fund Project of Shanghai Chest Hospital (2024IIT‑Q007). H.Yin. discloses support for the research of this work from the Shenzhen Medical Research Fund (SMRFB2502002, B2302042).
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Zhang, Y., Wang, S., Luo, T. et al. HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack. Nat Commun (2026). https://doi.org/10.1038/s41467-026-74022-y
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DOI: https://doi.org/10.1038/s41467-026-74022-y
