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.