Synergistic Interaction Between HPV-16 E7 Oncoprotein and Severe Vitamin A Deficiency in Regulating Adaptive Immunity...

Persistent infection with High-Risk Human Papillomavirus (HR-HPV), particularly HPV-16, is the main driver of cervical intraepithelial neoplasia (CIN) and cervical cancer (CC). However, HR-HPV infection alone is insufficient for malignant progression and nutritional cofactors such as Vitamin A deficiency, may influence cervical neoplasia progression through immune dysregulation. This study aimed to explore the interaction between HPV-16 E7 oncoprotein expression and severe Vitamin A Deficiency (VAD), as well as the effects of a Vitamin A-Normal Diet Reintegration (NDR) on adaptive immune regulation in cervical neoplasia using the K14E7 preclinical murine model. We found that VAD worsening cervical epithelial changes and impairs the cytotoxic ability of CD8⁺ T cells, which is marked by lower levels of granzyme B and increased expression of PI-9. These changes were accompanied by increase F4/80⁺ macrophage infiltration and elevated Foxp3 expression, suggesting enhanced Tregs immunosuppressor activity. Distinctly, NDR induced partial recovery of cervical epithelium architecture and the effector function of CD8⁺ T cells. Our results highlight Vitamin A as a key immunomodulator that influences the balance between immune surveillance and immune evasion of HPV-associated cervical carcinogenesis and suggests its potential relevance for preventive or adjuvant treatments in populations at high risk of CC.