journal article·2026-07Open access

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, Chaoqun Wang, Zhigang Feng, Zhongyu Li, Yongzhi Zhou, Zihao Li, Xinglong Li, Yongliang Hua, Yao Fu, Wei Tang, Yaohua Wu, Yong Ma

Advanced Science· Volume 13· Issue 37

Abstract

ABSTRACT Background & Aims : Cancer‐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 & Results : High 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 + T‐cell activity and synergized with anti‐PD‐L1 therapy in both patient‐derived xenografts (PDXs) and fibroblast‐specific NNMT‐knockout murine models. Conclusion : We 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.
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Research context

OpenAlex topics: Lipid metabolism and disorders · Cancer, Hypoxia, and Metabolism · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Minimally Invasive Hepatic Surgery The First Affiliated Hospital of Harbin Medical University Harbin China

Key Laboratory of Hepatosplenic Surgery Ministry of Education The First Affiliated Hospital of Harbin Medical University Harbin China

Department of Hepatobiliary Surgery Peking University People's Hospital Beijing China

Department of Anesthesiology Taizhou First People’s Hospital Taizhou China

Department of Hepatopancreatobiliary Surgery Affiliated Hangzhou First People's Hospital Zhejiang University School of Medicine Hangzhou China

Department of Hepatobiliary Surgery The Second Affiliated Hospital of Army Medical University Chongqing China

The First Department of General Surgery Affiliated Hospital of Inner Mongolia Minzu University Tongliao China

Department of Pediatric Surgery The First Affiliated Hospital of Harbin Medical University Harbin China

Department of Ultrasound The First Affiliated Hospital of Harbin Medical University Harbin China

International Health Care Center National Center for Global Health and Medicine Tokyo Japan

Hepato‐Biliary‐Pancreatic Surgery Division Department of Surgery The University of Tokyo Hospital Tokyo Japan

Department of Thyroid Surgery The First Affiliated Hospital of Harbin Medical University Harbin China

Funding

National Natural Science Foundation of China · Medical and Health Research Project of Zhejiang Province · Natural Science Foundation of Heilongjiang Province

References (37)

Show source-provided references
1. 10.3322/caac.2183410.3322/caac.21834 ↗
2. 10.1136/jitc‐2024‐01003510.1136/jitc‐2024‐010035 ↗
3. 10.1016/j.jcmgh.2023.01.00610.1016/j.jcmgh.2023.01.006 ↗
4. 10.1016/j.jconrel.2023.06.03610.1016/j.jconrel.2023.06.036 ↗
5. 10.1038/s41575‐023‐00821‐z10.1038/s41575‐023‐00821‐z ↗
6. 10.1016/j.intimp.2024.11320810.1016/j.intimp.2024.113208 ↗
7. 10.1002/cam4.289010.1002/cam4.2890 ↗
8. 10.1369/002215542097659010.1369/0022155420976590 ↗
9. 10.1038/s41586‐019‐1173‐810.1038/s41586‐019‐1173‐8 ↗
10. 10.1002/hep.3169710.1002/hep.31697 ↗
11. 10.1016/j.molcel.2021.01.01010.1016/j.molcel.2021.01.010 ↗
12. 10.1038/s41389‐022‐00415‐510.1038/s41389‐022‐00415‐5 ↗
13. 10.1002/advs.20241648410.1002/advs.202416484 ↗
14. 10.1158/0008‐5472.CAN‐19‐153210.1158/0008‐5472.CAN‐19‐1532 ↗
15. 10.1186/s13048‐022‐01060‐710.1186/s13048‐022‐01060‐7 ↗
16. 10.1182/blood‐2011‐01‐32871610.1182/blood‐2011‐01‐328716 ↗
17. 10.1016/j.drup.2024.10111610.1016/j.drup.2024.101116 ↗
18. 10.1002/hep.3179210.1002/hep.31792 ↗
19. 10.1002/hep.3209910.1002/hep.32099 ↗
20. 10.1016/j.gendis.2022.03.01910.1016/j.gendis.2022.03.019 ↗
21. 10.1039/D2NP00086E10.1039/D2NP00086E ↗
22. 10.1021/acs.biochem.8b0056110.1021/acs.biochem.8b00561 ↗
23. 10.1038/s41388‐021‐02172‐y10.1038/s41388‐021‐02172‐y ↗
24. 10.1158/0008‐5472.CAN‐21‐227310.1158/0008‐5472.CAN‐21‐2273 ↗
25. 10.7150/jca.5233810.7150/jca.52338 ↗
26. 10.1186/s12885‐020‐07343‐w10.1186/s12885‐020‐07343‐w ↗
27. 10.1002/hep.2447910.1002/hep.24479 ↗
28. 10.1016/j.ijbiomac.2024.13852310.1016/j.ijbiomac.2024.138523 ↗
29. 10.1186/1476‐4598‐13‐19610.1186/1476‐4598‐13‐196 ↗
30. 10.1155/2017/818723510.1155/2017/8187235 ↗
31. 10.1038/s41586‐019‐1678‐110.1038/s41586‐019‐1678‐1 ↗
32. 10.3389/fonc.2021.64755910.3389/fonc.2021.647559 ↗
33. 10.1038/d41586‐019‐03122‐110.1038/d41586‐019‐03122‐1 ↗
34. 10.1038/onc.2016.37110.1038/onc.2016.371 ↗
35. 10.1002/cac2.1241410.1002/cac2.12414 ↗
36. 10.1038/s41467‐025‐59968‐910.1038/s41467‐025‐59968‐9 ↗
37. 10.1016/j.jhep.2025.01.01210.1016/j.jhep.2025.01.012 ↗