TMEM242 orchestrates lymph node metastasis in oral squamous cell carcinoma through EMT and immune microenvironment remodeling

Lymph node metastasis (LNM) signifies poor prognosis in oral squamous cell carcinoma (OSCC), yet its underlying drivers remain incompletely understood. Here, we identify TMEM242 as a critical regulator of LNM through integrated multi-omics analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) revealed a distinct TMEM242-high epithelial subpopulation enriched in metastatic OSCC specimens, which correlated spatially with epithelial–mesenchymal transition (EMT) markers and predicted adverse clinical outcomes. Mechanistically, E2F1 directly binds to the TMEM242 promoter, activating its transcription. Upregulated TMEM242 promotes epithelial–mesenchymal transition via TGF-β/Smad signaling and concurrently fosters an immunosuppressive tumor microenvironment. In vivo , TMEM242-expressing tumors exhibited enhanced metastatic potential in a footpad transplantation model. Our results establish TMEM242 as a central orchestrator of LNM, driven by E2F1-mediated transcription and coordinating both EMT and immune evasion. TMEM242 thus represents a candidate prognostic biomarker and a potential therapeutic target for preventing metastasis in OSCC.