VCAN promotes the progression and recurrence of esophageal squamous cell carcinoma by remodeling the tumor microenvironment

Versican (VCAN), an extracellular matrix (ECM) proteoglycan, is implicated in tumor-related immunity and inflammation, but its specific function and mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Public databases, including Gene Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER), were used to analyze VCAN expression and its correlation with prognosis. Functional assays, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), wound healing, Transwell invasion, and tube formation assays, were conducted to evaluate the effects of VCAN on ESCC cell proliferation, migration, invasion, and angiogenesis in vitro. Nude mouse xenograft, lung metastasis, and tumor recurrence models were established to assess tumor growth, pulmonary metastasis, and cisplatin (CDDP) resistance in vivo. Immune cell profiles were analyzed using flow cytometry, immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA). VCAN was significantly upregulated in ESCC and was associated with poor survival. VCAN promoted ESCC cell proliferation, migration, invasion, angiogenesis, tumor growth, and pulmonary metastasis. Mechanistically, VCAN remodeled the immunosuppressive tumor microenvironment (TME) by inducing M2 macrophage polarization and impairing the activation and cytotoxicity of CD4⁺ and CD8⁺ T cells. In CDDP-treated mice, VCAN knockdown delayed tumor recurrence and alleviated the immunosuppressive TME, whereas VCAN overexpression accelerated recurrence. VCAN upregulation promoted ESCC progression and recurrence by modulating M2 macrophages and suppressing T cells. Targeting VCAN may represent a potential immunotherapy strategy for ESCC.