Human Papilloma Virus Does Not Fully Inactivate p53 Cellular Activity in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge. Inactivation of the tumor suppressor p53 is the most frequent driver event in this malignancy. p53 inactivation occurs either through TP53 mutations in human papilloma virus (HPV)-negative cases or via HPV-mediated p53 degradation in HPV-positive (HPV+) cases, where most tumors retain a wild-type (WT) TP53 allele. This underscores the critical role ofp53-regulated processes in HNSCC pathogenesis. Clinically, HPV+ HNSCC has significantly better outcomes than HPV-negative disease. However, approximately 10% of HPV+ HNSCC tumors harbor TP53 mutations, suggesting selective pressure to suppress p53 signaling beyond viral degradation. In this study, we demonstrate that HPV+ TP53-WTHNSCC cells have residual, tumor suppressive p53 activity. Clinically, patients with HPV+ TP53-WT tumors exhibit significantly better survival than those with HPV+ TP53-mutantor HPV-negative tumors. In vitro, WT p53 loss in HPV+ HNSCC cells enhances proliferation, migration, and invasion, and transcriptomic analysis confirms ongoing p53-dependent gene regulation. HPV+ TP53-WT tumors also display tumor-suppressive gene methylation patterns, fewer chromosomal alterations, and reduced PI3K-AKT signaling compared to TP53-mutant HPV+ cases. Notably, p53 loss increases expression of the PI3K catalytic subunit p110α, suppresses the PI3K-AKT inhibitor INPP5D, and sensitizes cells to pharmacologic PI3Kinhibition. Together, our findings challenge the prevailing view that p53 is completely inactivated in HPV+ HNSCC and reveal tumor suppressive, p53-driven mechanisms that persist in these tumors. These insights highlight a potential role for TP53-based stratification in guiding treatment decisions and suggest new therapeutic vulnerabilities in HPV+ HNSCC.