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

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: 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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Publication Details

Journal
Advanced Science
Published
2026-04-14
DOI
https://doi.org/10.1002/advs.202521418
Primary Topic
Lipid metabolism and disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Miaoyu Bai, Hongjun Yu, Yaohua Wu, Zhanzhi Meng et al.
Advanced Science
Lipid metabolism and disorders
article

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

Miaoyu Bai, Hongjun Yu, Yaohua Wu, Zhanzhi Meng, Yong Ma, Shanjia Ke, Z Li, Zhigang Feng, Yongliang Hua, Zihao Li, Xinglong Li, Baolin Qian, Yao Fu, Bing Yin, Jinwen Yang, Wei Tang, Hui Zhu, Yongzhi Zhou, Shounan Lu, Yanan Xu
article en

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: 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.

Advanced Science
Inner Mongolia University for Nationalities (CN), Army Medical University (CN), Harbin Medical University (CN), Dalian Medical University (CN), Peking University (CN), National Center for Global Health and Medicine (JP), Second Affiliated Hospital of Chongqing Medical University (CN), University of Tokyo Hospital (JP), Peking University People's Hospital (CN), Taizhou First People's Hospital (CN), Affiliated Hangzhou First People's Hospital, Westlake University, School of Medicine (CN), First Affiliated Hospital of Harbin Medical University (CN), Chongqing Medical University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Heilongjiang Province, Medical and Health Research Project of Zhejiang Province
Good health and well-being
Openalex Percentile: Top 24%
Lipid metabolism and disorders
DOIOpen Access PDFOpenAlex
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