Single-cell spatial transcriptomics identifies SERPINE1 as a vascular endothelial mediator of cisplatin resistance in head and neck squamous cell carcinoma

BACKGROUND: Cisplatin resistance remains a major obstacle in head and neck squamous cell carcinoma (HNSCC), yet the contribution of the vascular microenvironment and its variation across HPV statuses remains unclear. METHODS: We integrated single-cell RNA sequencing, spatial transcriptomics, and bioinformatics analyses to characterize cisplatin resistance-associated cellular states in HNSCC. Cisplatin resistance scoring, pseudotime analysis, transcriptional regulatory network analysis, and cell-cell communication analysis were used to identify resistant subpopulations. Spatial localization, survival analysis, immune infiltration assessment, and drug sensitivity prediction were further performed to evaluate key candidate genes. RESULTS: Cisplatin resistance signals were preferentially enriched in tumor endothelial cells and were stronger in HPV-negative HNSCC. Endothelial cells with high resistance scores exhibited enhanced angiogenesis, extracellular matrix remodeling, hypoxia, and inflammatory programs. Multidimensional screening identified SERPINE1 as a key resistance-associated endothelial gene, showing significant upregulation and positive correlation with resistance scores. Single-cell and spatial transcriptomic analyses consistently demonstrated vascular-associated enrichment of SERPINE1, particularly in HPV-negative tumors. High SERPINE1 expression was associated with poor survival and an immunosuppressive tumor microenvironment. Drug sensitivity prediction suggested increased sensitivity of SERPINE1-high tumors to EGFR/SRC- and MAPK-pathway inhibitors, whereas no significant differences were observed for conventional cytotoxic agents. CONCLUSION: SERPINE1 defines a tumor endothelial state associated with cisplatin resistance in HNSCC and may contribute to HPV-related differences in the vascular microenvironment, providing a potential basis for therapeutic stratification.