HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack

Yajuan Zhang; Siyao Wang; Tianhang Luo; Haitang Yang; Yongqiang Wang; Tong Rong; Miaowen Zou; Qizhen Fei; Zhonggang Shi; YiFei Zhu; Xin Zhou; Hong Gao; Yun Zhao; Zhengjiang Zhu; Huiyong Yin; Guangchuan Wang; Chenqi Xu; Xiujuan Qu; Feng Yao; Weiwei Yang

doi:10.1038/s41467-026-74022-y

HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack

Yajuan Zhang^* (Co-first Author)
, Siyao Wang (Co-first Author)
, Tianhang Luo (Co-first Author)
, Haitang Yang (Co-first Author)
, Yongqiang Wang
, Tong Rong
, Miaowen Zou
, Qizhen Fei
, Zhonggang Shi
, YiFei Zhu
, Xin Zhou
, Hong Gao
, Yun Zhao
, Zhengjiang Zhu
, Huiyong Yin
, Guangchuan Wang
, Chenqi Xu
, Xiujuan Qu^*
, Feng Yao^*
, Weiwei Yang^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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. © The Author(s) 2026

Original language	English
Article number	7204
Journal	Nature Communications
Volume	17
Online published	5 Jun 2026
DOIs	https://doi.org/10.1038/s41467-026-74022-y
Publication status	Published - 2026

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., Yang, H., Wang, Y., Rong, T., Zou, M., Fei, Q., Shi, Z., Zhu, Y., Zhou, X., Gao, H., Zhao, Y., Zhu, Z., Yin, H., Wang, G., Xu, C., Qu, X., Yao, F., & Yang, W. (2026). HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack. Nature Communications, 17, Article 7204. https://doi.org/10.1038/s41467-026-74022-y

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title = "HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack",

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. {\textcopyright} The Author(s) 2026",

author = "Yajuan Zhang and Siyao Wang and Tianhang Luo and Haitang Yang and Yongqiang Wang and Tong Rong and Miaowen Zou and Qizhen Fei and Zhonggang Shi and YiFei Zhu and Xin Zhou and Hong Gao and Yun Zhao and Zhengjiang Zhu and Huiyong Yin and Guangchuan Wang and Chenqi Xu and Xiujuan Qu and Feng Yao and Weiwei Yang",

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language = "English",

volume = "17",

journal = "Nature Communications",

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TY - JOUR

T1 - HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack

AU - Zhang, Yajuan

AU - Wang, Siyao

AU - Luo, Tianhang

AU - Yang, Haitang

AU - Wang, Yongqiang

AU - Rong, Tong

AU - Zou, Miaowen

AU - Fei, Qizhen

AU - Shi, Zhonggang

AU - Zhu, YiFei

AU - Zhou, Xin

AU - Gao, Hong

AU - Zhao, Yun

AU - Zhu, Zhengjiang

AU - Yin, Huiyong

AU - Wang, Guangchuan

AU - Xu, Chenqi

AU - Qu, Xiujuan

AU - Yao, Feng

AU - Yang, Weiwei

PY - 2026

Y1 - 2026

N2 - 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. © The Author(s) 2026

AB - 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. © The Author(s) 2026

U2 - 10.1038/s41467-026-74022-y

DO - 10.1038/s41467-026-74022-y

M3 - RGC 21 - Publication in refereed journal

C2 - 42248910

SN - 2041-1723

VL - 17

JO - Nature Communications

JF - Nature Communications

M1 - 7204

ER -

HMGCS1 drives cholesterol-dependent membrane repair and shields tumor cells from lymphocyte attack

Abstract

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