Genomic enrichment and functional impact of TP53 and CYLD alterations in recurrent and metastatic HPV-associated head and neck cancer

R/M HPV+ HNSCC is genomically and functionally shaped by 2 axes with therapeutic implications: TP53 gain-of-function mutations promote metastatic phenotypes and cisplatin resistance, while CYLD loss defines an HPV-specific subset with enhanced radiation sensitivity and immune activation. These data support using TP53 and CYLD as predictive biomarkers to guide investigation into precision strategies for systemic therapy choices, p53-targeted/Wee1 strategies, and radiotherapy-immunotherapy combinations in high-risk or R/M HPV+ HNSCC.