Advances in immunotherapy for HPV-associated malignancies: emerging strategies and clinical progress

Human papillomavirus (HPV) is the principal etiological factor in the majority of cervical, oropharyngeal, anal, and vulvar cancers. Persistent infection with high-risk HPV types promotes immune evasion, malignant transformation, and tumor progression. Currently licensed prophylactic HPV vaccines, based on L1 virus-like particles, are highly effective at preventing new infections and HPV-associated neoplastic disease through the induction of neutralizing antibodies. However, they do not eradicate established infections or preexisting lesions. These limitations have driven the development of therapeutic HPV vaccines and adoptive T-cell strategies aimed at eliciting robust cell-mediated immunity against HPV-associated malignancies. The viral oncoproteins E6 and E7 are attractive therapeutic targets. They disrupt cell-cycle control and are consistently expressed in HPV-driven precancerous and cancerous lesions. In this review, we provide a comprehensive overview of therapeutic HPV vaccines-including viral and bacterial vectors, DNA and RNA constructs, peptide/protein vaccines, and cell-based approaches-all designed to target E6 and E7, while considering the benefits and limitations of each platform. We also present an in-depth analysis of adoptive T-cell therapies, highlighting Immuno-STAT, a peptide-HLA fusion platform for the direct expansion of HPV-specific CD8⁺ T cells. Furthermore, we discuss rational combination strategies that integrate these modalities with immune checkpoint inhibitors and other immunomodulatory agents, including the bifunctional PD-L1/TGF-β inhibitor bintrafusp alfa, to overcome key barriers and enhance clinical efficacy. Overall, this review synthesizes current evidence and outlines future directions for the development of more precisely tailored HPV-specific immunotherapies in cancer treatment.