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

  • Nat Commun. 2026 Jun 5. doi: 10.1038/s41467-026-74022-y.
Yajuan Zhang  #  1  2 ,  Siyao Wang  #  3 ,  Tianhang Luo  #  4 ,  Haitang Yang  #  5 ,  Yongqiang Wang  6 ,  Tong Rong  7 ,  Miaowen Zou  3 ,  Qizhen Fei  5 ,  Zhonggang Shi  7 ,  YiFei Zhu  8  9 ,  Xin Zhou  10 ,  Hong Gao  3 ,  Yun Zhao  3 ,  Zhengjiang Zhu  10 ,  Huiyong Yin  11 ,  Guangchuan Wang  3 ,  Chenqi Xu  3 ,  Xiujuan Qu  12 ,  Feng Yao  13 ,  Weiwei Yang  14  15  16
Affiliations
  • 1. Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, 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, China. [email protected].
  • 2. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 3. Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, 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, China.
  • 4. Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
  • 5. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6. Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
  • 7. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 9. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 10. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 11. Department of Biomedical Sciences, College of Biomedicine, Institute of Digital Medicine, Tung Biomedical Science Center, The Shenzhen Research Institute and Futian Research Institute, City University of Hong Kong, Hong Kong, China.
  • 12. Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China. [email protected].
  • 13. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 14. Key Laboratory of Multi-cell Systems, Shanghai Key Laboratory of Molecular Andrology, 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, China. [email protected].
  • 15. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. [email protected].
  • 16. Shanghai Academy of Natural Sciences (SANS), Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42248910 DOI: 10.1038/s41467-026-74022-y
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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