Evidence map›Paper›PMID 42248910›Full record

ArticleNature communications2026

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 and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Yajuan Zhang *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. zhangyajuan2013@sibcb.ac.cn.ORCID http://orcid.org/0009-0009-5002-2535
Siyao Wang *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.
Tianhang Luo *Department of Gastrointestinal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
Haitang Yang *Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.ORCID http://orcid.org/0000-0002-8732-5910
Yongqiang WangFrontier Medical Center, Tianfu Jincheng Laboratory, Chengdu, China.
Tong RongShanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Miaowen ZouKey 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.
Qizhen FeiDepartment of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhonggang ShiShanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
YiFei ZhuDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Xin ZhouInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Hong GaoKey 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.
Yun ZhaoKey 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.ORCID http://orcid.org/0000-0002-7807-6094
Zhengjiang ZhuInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.ORCID http://orcid.org/0000-0002-3272-3567
Huiyong YinDepartment 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.ORCID http://orcid.org/0000-0001-7049-1560
Guangchuan WangKey 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.ORCID http://orcid.org/0000-0001-5315-1599
Chenqi XuKey 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.ORCID http://orcid.org/0000-0002-4968-6782
Xiujuan QuDepartment of Medical Oncology, the First Hospital of China Medical University, Shenyang, China. xjqu@cmu.edu.cn.ORCID http://orcid.org/0009-0005-9366-2314
Feng YaoDepartment of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yaofeng@shsmu.edu.cn.ORCID http://orcid.org/0000-0002-9635-9581
Weiwei YangKey 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. wyang@sibcb.ac.cn.ORCID http://orcid.org/0000-0002-1661-9137

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Cell MembraneCholesterolHydroxymethylglutaryl-CoA SynthaseLung NeoplasmsLymphocytesAnimalsCell Line, TumorHumansKiller Cells, NaturalMicePerforinTumor EscapeCholesterolHydroxymethylglutaryl-CoA SynthasePerforin

Identifiers

PMID42248910
PMCPMC13396504

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.