Multi-omics identifies VMP1 as a tumor-intrinsic biomarker associated with metastatic progression and immune microenvironment remodeling in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) frequently exhibits metastatic progression and develops an immunosuppressive microenvironment. However, the tumor cell-intrinsic factors contributing to metastasis-associated immune remodeling remain incompletely understood. Here, we integrated two independent single-cell RNA-seq cohorts (GSE243933 and GSE181919) to compare primary and metastatic HNSCC ecosystems and identified vacuole membrane protein 1 (VMP1) as a malignant cell-intrinsic gene consistently upregulated across metastatic contexts. In TCGA-HNSCC and two GEO cohorts (GSE65858 and GSE117973), high VMP1 expression was associated with poor prognosis and enrichment of invasion-related programs, including epithelial-mesenchymal transition (EMT) and TNFα/NF-κB signaling, and was also associated with decreased CD8⁺ T-cell infiltration and impaired effector features. In an independent HNSCC tissue cohort, immunohistochemistry confirmed elevated VMP1 protein expression in tumors and its association with advanced clinicopathological features and unfavorable survival. Functionally, gain- and loss-of-function experiments in SCC25 and CAL27 cells showed that VMP1 enhances proliferation, migration, and invasion, accompanied by EMT-like marker switching, increased RelA/p65 phosphorylation, and elevated PD-L1 expression. Collectively, VMP1 identifies a metastasis-associated tumor-intrinsic factor associated with invasive progression and reduced CD8⁺ T-cell activity. The concomitant NF-κB activation and PD-L1 induction support a potential VMP1-associated NF-κB/PD-L1 link that may contribute to the association between invasion-related programs and immune modulation. These findings support the potential biomarker relevance of VMP1 and provide a rationale for further mechanistic and clinical investigation in HNSCC.