In Nature Genetics, an international team led by investigators at Washington University School of Medicine and the Weizmann Institute of Science outline cellular and molecular features found in forms of oropharyngeal squamous cell carcinoma (OSCC) cases marked by human papillomavirus (HPV) infection, a form of the cancer that tends to have more favorable outcomes than head and neck squamous cell carcinomas. Using single-cell RNA sequencing, the researchers assessed HPV-positive and -negative forms of oropharyngeal HNSCC. Along with cellular and chromosomal features marking the HNSCC subtypes assessed more broadly, the authors saw a range of HPV expression patterns in the subset of HPV-positive samples, including tumor subclones with damped down or missing viral gene expression. "[A] subset of HPV-related OPSCCs responds poorly to treatment and recur, underscoring the need for a deeper understanding of these tumors and the development of new therapeutic approaches," they explain, noting that the current results "suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications."