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

Yajuan Zhang1,2, Siyao Wang3, Tianhang Luo4

  • 1Key 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. zhangyajuan2013@sibcb.ac.cn.

Nature Communications
|June 5, 2026
PubMed

Insights

Tumor cells repair plasma membrane damage using HMGCS1, which synthesizes cholesterol. This repair mechanism helps tumors evade immune attack and reduces immunotherapy effectiveness. Targeting HMGCS1 may improve cancer treatments.

Area of Science:

  • Immunology
  • Cancer Metabolism
  • Cell Biology

Background:

  • Cytotoxic lymphocytes induce tumor cell death via plasma membrane (PM) pore formation.
  • Tumor cell metabolism's role in PM repair and immune evasion remains largely unknown.
  • Understanding PM repair mechanisms is crucial for enhancing cancer immunotherapies.

Purpose of the Study:

  • To identify metabolic enzymes involved in tumor cell plasma membrane repair.
  • To elucidate the mechanism by which tumor metabolism facilitates immune evasion.
  • To explore the therapeutic potential of targeting identified metabolic pathways in cancer immunotherapy.

Main Methods:

  • Functional screening of 111 metabolic enzymes to identify those involved in PM repair.
  • Investigating the role of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) in cholesterol synthesis and PM repair.
  • Assessing the impact of HMGCS1 inhibition on tumor cell resistance to lymphocyte-mediated killing.
  • Analyzing patient data to correlate molecular markers with immunotherapy response.

Main Results:

  • HMGCS1 was identified as critical for repairing perforin-induced PM damage.
  • HMGCS1 promotes de novo cholesterol synthesis, enhancing tumor cell survival and resistance to immune attack.
  • Cholesterol directly binds CHMP4B, facilitating PM repair.
  • Elevated HMGCS1 expression and associated markers correlate with reduced efficacy of anti-PD-1 immunotherapy in lung cancer patients.
  • Oncogenic activation, cytokines, and hypoxia induce c-Jun activation, up-regulating HMGCS1.

Conclusions:

  • HMGCS1-driven cholesterol synthesis is a key tumor immune evasion mechanism.
  • Targeting HMGCS1 can enhance tumor cell susceptibility to immune-mediated killing.
  • HMGCS1 represents a potential therapeutic target to improve the effectiveness of cancer immunotherapies.

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