High-risk HPV oncoproteins E6 and E7 and their interplay with the innate immune response: Uncovering mechanisms of immune evasion and therapeutic prospects

: Human papillomaviruses (HPVs) are double-stranded DNA (dsDNA) tumor viruses causally associated with 5% of human cancers, comprising both anogenital and upper aerodigestive tract carcinomas. Despite the availability of prophylactic vaccines, HPVs continue to pose a significant global health challenge, primarily due to inadequate vaccine access and coverage. These viruses can establish persistent infections by evading both the intrinsic defenses of infected tissues and the extrinsic defenses provided by professional innate immune cells. Crucial for their evasion strategies is their unique intraepithelial life cycle, which effectively shields them from host detection. Thus, strategies aimed at reactivating the innate immune response within infected or transformed epithelial cells, particularly through the production of type I interferons (IFNs) and lymphocyte-recruiting chemokines, are considered viable solutions to counteract the adverse effects of persistent infections by these oncogenic viruses. This review focuses on the complex interplay between the high-risk HPV oncoproteins E6 and E7 and the innate immune response in epithelial cells and HPV-associated cancers. In particular, it details the molecular mechanisms by which E6 and E7 modulate the innate immune response, highlighting significant progress in our comprehension of these processes. It also examines forward-looking strategies that exploit the innate immune system to ameliorate existing anticancer therapies, thereby providing crucial insights into future therapeutic developments.