The discriminating role of extracellular vesicles in HPV-dependent and HPV-independent head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is the seventh most frequently diagnosed cancer worldwide, contributing to approximately 400,000 deaths annually. Recently, the involvement of human papillomavirus (HPV) in the etiopathogenesis of this malignancy, particularly in oropharyngeal squamous cell carcinoma (OPSCC), has been emphasized. In parallel, the potential role of extracellular vesicles (EVs) in the initiation and progression of HNSCCassociated with HPV infection has emerged. EVs are small, membrane-bound vesicles secreted by all cell types, that transport biologically significant cargo, including proteins and nucleic acids. EVs produced by tumor cells interact with non-malignant cells and reprogram the tumor microenvironment, inducing immune suppression, promoting angiogenesis, and facilitating tumor metastasis. Tumor-derived EVs carry DNA and may be responsible for the horizontal transfer of viral structural and functional components, including the E6 and E7 oncoproteins to other cells. The interplay between the mechanisms associated with the HPV replication cycle, EV biogenesis and release, and carcinogenesis represents a novel and still poorly understood area in the investigation of HNSCC development and progression. This review synthesizes recent findings on the distinct roles tumor-derived EVs appear to play in both HPV-dependent and HPV-independent HNSCC.