NECTIN-4 orchestrates macrophage-mediated tumor plasticity in oral squamous cell carcinoma

Tumor associated macrophages (TAM) are key regulator of the tumor microenvironment (TME), however, the upstream factors that contribute to the polarization and functional reprogramming in oral squamous cell carcinoma (OSCC) remain largely unclear. This study evaluates the role of Nectin-4 in modulating tumor-immune interactions and its impact on OSCC progression. Detailed transcriptomic data from The Cancer Genome Atlas (TCGA)-OSCC dataset revealed that high NECTIN-4 expression was associated with enrichment of pathways involved in epithelial mesenchymal transition (EMT), angiogenesis, and stemness, and was inversely correlated with inflammatory signaling and immune infiltration.Additionally, single-cell transcriptomic analyses demonstrated an increase in macrophages, solely focused on the stroma, in Nectin-4 high tumors. Consistently, SCC-9 cells exhibited high levels of Nectin-4 and Nectin-4 enriched conditioned media (CM) derived from SCC-9 cells induced polarization of THP-1 monocytes toward a TAMs-like phenotype, characterized by increased CD163 expression and elevated secretion of immunomodulatory cytokines such as CCL-2. Co-culture of TAMs with SCC-9 cells promoted tumor aggressiveness, as evidenced by increased expression of EMT markers (E-cadherin, N-cadherin, vimentin) and stem cell markers (CD133, OCT4), invasion and cytoskeletal remodeling. These TAMs also enhanced angiogenesis in cancer cells by increasing the expression of VEGF-A, angiopoietin-1 (Ang-1), and TGF-β, along with in ovo neovascularization and promoting endothelial tube formation. Overall, the study identifies Nectin-4 as a key mediator of tumor-immune crosstalk in OSCC, driving macrophage enrichment, immune suppression and pro-tumorigenic signaling. Therefore, targeting Nectin-4 signaling could be a new approach to restore anti-tumor immunity and inhibit OSCC progression.