Interplay between hypoxia, RNA methylation, and HPV in head and neck squamous cell carcinomas: drivers of oncogenesis and resistance to therapy.

Head and neck squamous cell carcinoma (HNSCC) encompasses a diverse group of tumors with varying etiology, biology, and response to therapy. Among its subtypes, human papillomavirus positive HNSCC is associated with better prognosis and enhanced sensitivity to radiotherapy, chemotherapy, and immunotherapy. However, resistance still occurs and is often driven by complex molecular mechanisms that remain incompletely understood. Recent evidence highlights the pivotal role of RNA modifications-particularly N6-methyladenosine (m⁶A)-in regulating key processes such as gene expression, immune response, and treatment resistance. Dysregulation of m⁶A machinery, including methyltransferases (METTL3, METTL14), demethylases (FTO, ALKBH5), and m⁶A readers (YTHDFs, IGF2BPs), has been implicated in oncogenesis, immune evasion, and therapy failure in multiple cancers, including HNSCC. These epitranscriptomic changes intersect with hypoxia-driven signaling pathways, which reshape the tumor microenvironment, promote immunosuppression, and impair DNA repair, further contributing to resistance to conventional and targeted therapies. Moreover, in HPV-related HNSCC, viral oncoproteins modulate both RNA methylation and host immune dynamics, creating a unique biological context where m⁶A modifications may serve as mediators of HPV-specific oncogenic programs and therapeutic vulnerabilities. This review integrates current knowledge on the interplay between hypoxia, m⁶A RNA methylation, and HPV infection in HNSCC, emphasizing their combined role in shaping tumor progression and resistance. A deeper understanding of these pathways may offer new opportunities for biomarker discovery and the development of rational combination therapies. See also the graphical abstract(Fig. 1).