Evidence map›Paper›PMID 41980209›Full record

ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026

Cancer-Associated Fibroblasts Promote Tumor Immunosuppression in Hepatocellular Carcinoma via the NNMT-ANGPTL4 Axis.

Shounan Lu, Shanjia Ke, Hongjun Yu, Zhanzhi Meng, Miaoyu Bai, Yanan Xu, Hui Zhu, Jinwen Yang, Baolin Qian, Bing Yin and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. Review
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

21 authors.

Shounan LuDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Shanjia KeKey Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Hongjun YuDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Zhanzhi MengDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Miaoyu BaiDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Yanan XuKey Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Hui ZhuDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Jinwen YangDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Baolin QianDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Bing YinDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Chaoqun WangKey Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Zhigang FengKey Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Zhongyu LiDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Yongzhi ZhouDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Zihao LiDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Xinglong LiDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Yongliang HuaKey Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Yao FuDepartment of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Wei TangInternational Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan.
Yaohua WuKey Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
Yong MaDepartment of Minimally Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.ORCID https://orcid.org/0000-0002-6508-508X

Funding

Basic scientific research projects of provincial higher education institutions in Heilongjiang Province 2023-KYYWF-0151Chen Xiaoping Foundation for the Development of Science and Technology of Hubei Province CXPJJH122002-025Key Research and Development Program of Heilongjiang Province 2024ZX12C28Medical and Health Research Project of Zhejiang Province 2024KY1324National Natural Science Foundation of China 81502605National Natural Science Foundation of China 82370643National Natural Science Foundation of China 82403104National Natural Science Foundation of China 82403110National Outstanding Youth Science Fund Project of National Natural Science Foundation of China 82525068Natural Science Foundation of Heilongjiang Province LC2018037Natural Science Foundation of Heilongjiang Province PL2024H069Scientific Foundation of the First Affiliated Hospital of Harbin Medical University HYD2020JQ0007Scientific Foundation of the First Affiliated Hospital of Harbin Medical University HYD2020JQ0012
6 · The paper itself

Abstract

BACKGROUND &

aimsCancer-associated fibroblasts (CAFs) drive immunosuppression in hepatocellular carcinoma (HCC). However, their metabolic regulation remains poorly defined. We investigated the role of nicotinamide N-methyltransferase (NNMT) in CAFs. APPROACH &

resultsHigh NNMT expression in CAF tissues was confirmed by western blotting and immunofluorescence staining. Primary CAFs from HCC patients, single-cell RNA-seq (GSE149614), patient-derived organoids (PDOs), and fibroblast-specific NNMT-knockout mice were integrated by metabolomic analyses. NNMT in CAFs binds EZH2 and impedes its nuclear translocation, thereby reducing H3K27me3 enrichment at the promoter of angiopoietin-like 4 (ANGPTL4) to increase ANGPTL4 secretion. Secreted ANGPTL4 engages GLUT1 in HCC cells, activating aerobic glycolysis and increasing histone H3K18la levels. This epigenetic reprogramming transcriptionally upregulates PD-L1 expression, thereby facilitating tumor immune evasion. Additionally, CAF-derived ANGPTL4 promotes angiogenesis in HCC. Therapeutically, targeting the NNMT-ANGPTL4 axis restored CD8

conclusionWe identified an NNMT-ANGPTL4-driven metabolic-epigenetic cascade in CAFs that induces PD-L1-mediated immune evasion, providing a therapeutic strategy to overcome resistance to immunotherapy in patients with HCC.

Indexed as

Angiopoietin-Like Protein 4Cancer-Associated FibroblastsCarcinoma, HepatocellularLiver NeoplasmsAnimalsHumansMiceMice, KnockoutAngiopoietin-Like Protein 4ANGPTL4 protein, humanANGPTL4HCChistone lactylationImmune evasionNNMT

Identifiers

PMID41980209
PMCPMC13334667

What OpenQuestion holds

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Registered trials

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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.