HPV-associated extracellular vesicles and the tumor microenvironment: mechanisms of immune modulation and translational implications

Human papillomavirus infections are a major cause of cervical cancer and are also associated with several anogenital and oropharyngeal malignancies. Persistent infection with high-risk HPV types and sustained expression of viral oncoproteins E6 and E7 contribute to malignant transformation. Extracellular vesicles are increasingly recognized as important mediators of intercellular communication and can transfer proteins, nucleic acids, lipids, and other regulatory molecules between cells. HPV-associated changes in EV cargo, such as viral transcripts, may influence immune and stromal cells within the tumor microenvironment. Experimental studies have implicated HPV-associated EVs in the regulation of dendritic cell function, macrophage polarization, T-cell responses, immune checkpoint signaling, chronic inflammation, and mechanisms related to viral persistence and immune evasion. Cell-based and preclinical studies also suggest that EVs released by HPV-positive tumor cells may contribute to related disorders including angiogenesis and metastatic progression. On the other hand, human studies have primarily provided observational evidence linking EV-associated molecular profiles with HPV status or disease characteristics. Beyond these mechanistic insights, a growing body of work explores the translational potential of EVs, including their use as liquid-biopsy biomarkers and as engineered delivery platforms such as Nefmut-based vesicles carrying HPV16 E7 that elicit protective CD8 + T-cell responses in preclinical models. This narrative review, with emphasis on tumor-immune interactions, and also discusses emerging diagnostic and therapeutic applications together with the methodological and clinical barriers that must be addressed before EV-based strategies can be translated into routine practice.