Spatial analysis of head and neck cancer identifies two ecosystems with distinct modes of epithelial-to-mesenchymal transition

Head and neck squamous cell carcinoma (HNSCC) shows substantial intra- and inter-tumoral heterogeneity. We mapped tumor architecture across HPV-positive and HPV-negative HNSCC through spatial transcriptomics (n = 26). HPV-positive tumors display hypercellularity, higher lymphocyte presence, enriched hypoxia and reduced partial epithelial-to-mesenchymal transition (p-EMT) in malignant cells. We observed two distinct spatial architectures of p-EMT: p-EMT edge, where p-EMT is coupled to fibroblasts at the invasive front via TGFβ, and p-EMT core, in which tumor-infiltrating immunosuppressive macrophages and neutrophils induce p-EMT via oncostatin M in the core of tumor nests. These two p-EMT patterns were consistent across multiple samples from the same tumor, suggesting they are tumor-wide features. Together, these findings reveal that distinct interactions in the tumor microenvironment converge on a similar p-EMT cellular phenotype, but in a different spatial pattern that may have potential biological and clinical implications for our understanding of invasion, immune modulation and new targeted therapeutics for HNSCC. A spatially resolved analysis of HPV-positive and HPV-negative head and neck cancers identifies two distinct spatial localizations of partial epithelial-to-mesenchymal transition, in the tumor core or edge, which associate with specific immune contexts and clinical outcomes.