From infection to immortality: The role of HPV and telomerase in head and neck cancer

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of malignancies with multifactorial aetiologies. High-risk human papillomavirus (hrHPV) infections, particularly HPV16, and the dysregulation of telomerase activity, specifically through its catalytic subunit, telomerase reverse transcriptase (TERT) are among the key contributors to HNSCC development and progression. HPV promotes oncogenesis via the E6 and E7 oncoproteins, which inactivate tumour suppressors TP53 and RB1, leading to unchecked cellular proliferation. Concurrently, telomerase activation plays a critical role in HNSCC by maintaining telomere length, thus enabling cellular immortality, and facilitating tumour development and progression. The interplay between HPV and telomerase is significant; HPV oncoprotein E6 enhances telomerase activity through multiple regulatory mechanisms, including upregulating TERT expression. Beyond telomere maintenance, TERT influences signalling pathways, cellular metabolism, and the tumour microenvironment, contributing to aggressive tumour behaviour and poor prognosis. This review integrates the roles of HPV and telomerase in HNSCC, focusing on their molecular mechanisms and interactions that drive carcinogenesis and influence disease progression. Understanding the synergistic effects of HPV and TERT in HNSCC may be crucial for risk stratification, prognostic assessment, and the development of novel therapeutic strategies targeting these specific molecular pathways.