Small Extracellular Vesicles Derived from Helicobacter Pylori‐Infected Gastric Cancer Cells Induce Lymphangiogenesis and Lymphatic Remodeling via Transfer of miR‐1246

Abstract Lymph node metastasis (LNM) is a significant barrier to the prognosis of patients with gastric cancer (GC). Helicobacter pylori (H. pylori) ‐positive GC patients experience a higher rate of LNM than H. pylori ‐negative GC patients. However, the underlying mechanism remains unclear. Based on the findings of this study, H. pylori ‐positive GC patients have greater lymphangiogenesis and lymph node immunosuppression than H. pylori ‐negative GC patients. In addition, miR‐1246 is overexpressed in the plasma small extracellular vesicles (sEVs) of H. pylori ‐positive GC patients, indicating a poor prognosis. Functionally, sEVs derived from GC cells infected with H. pylori deliver miR‐1246 to lymphatic endothelial cells (LECs) and promote lymphangiogenesis and lymphatic remodeling. Mechanistically, miR‐1246 suppresses GSK3β expression and promotes β‐Catenin and downstream MMP7 expression in LECs. miR‐1246 also stabilizes programmed death ligand‐1 (PD‐L1) by suppressing GSK3β and induces the apoptosis of CD8 + T cells. Overall, miR‐1246 in plasma sEVs may be a novel biomarker and therapeutic target in GC‐LNM.