Distinct single-cell cellular states and ecosystems linked to HPV status distinguish therapeutic vulnerability of head and neck squamous cell carcinoma.

Human papillomavirus (HPV) infection plays a significant role in shaping the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC). However, the heterogeneity of cellular states and ecosystems within the tumor microenvironment of HPV-infected HNSCC is still largely unknown. Using the EcoTyper framework, we perform an extensive evaluation of HPV-related cellular profiles and cellular ecotypes (CEs) in HNSCC. Single-cell RNA sequencing reveals 46 unique states across 12 principal cell types. Spatial transcriptomics confirm the spatial correlation of cellular states from the same ecotype. Moreover, prognostic and drug sensitivity analyses reveal the clinically relevant and therapeutic vulnerabilities of cellular status for patients with different HPV statuses. In conclusion, our findings provide insights into the different cellular organizations and microenvironments of HPV-related HNSCC, with potential implications for the development of biomarkers and precision therapies.