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

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.