Epigenetic Activation of ANGPTL4 Drives EBV‐Negative Gastric Cancer via Neutrophil Recruitment and NET Release via Stabilizing ANXA5

ABSTRACT

EBV‐positive (EBVaGC) and EBV‐negative (EBVnGC) gastric cancers exhibit distinct clinical outcomes, prognostic features, and immune infiltration landscapes; however, the molecular mechanisms driving these subtype differences, as well as the subtype‐specific epigenetic regulation and biological functions of ANGPTL4 within the immune microenvironment, remain unclear. Here, through integrated analysis of multi‐omics data, we discovered that EBV infection induces marked hypermethylation at the ANGPTL4 promoter, leading to transcriptional silencing of ANGPTL4 in EBVaGC. Conversely, hypomethylation‐mediated ANGPTL4 overexpression is clinically associated with poor prognosis and distant metastasis in EBVnGC. Mechanistically, the C‐terminal secreted form (cANGPTL4) promotes GC progression by enhancing proliferation, epithelial‐mesenchymal transition (EMT), and neutrophil recruitment. Clinically, ANGPTL4 expression is positively correlated with neutrophil infiltration and neutrophil extracellular traps (NETs) levels in GC. Spatial transcriptomics and immunohistochemistry (IHC) analyses confirmed the spatial colocalization of ANGPTL4 with tumor‐infiltrating neutrophils. cANGPTL4 mediates tumor‐associated neutrophil (TAN) recruitment via the NF‐κB/CXCL8 axis and directly binds and stabilizes neutrophil‐derived ANXA5 to facilitate NET release, thereby driving GC progression. In conclusion, ANGPTL4 represents a potential intervention target for EBVnGC. Targeting ANGPTL4 may exert dual anti‐tumor effects by directly suppressing GC proliferation, EMT, and metastasis, and by remodeling the immunosuppressive microenvironment via attenuating TANs infiltration and NET release.