TY - JOUR

T1 - Advances in immunotherapy for HPV-associated malignancies: emerging strategies and clinical progress

AU - Alsalloum, Alaa

AU - Zakhareva, Alena

AU - Lopatnikova, Julia

AU - Sennikov, Sergey

N1 - Alsalloum A, Zakhareva A, Lopatnikova J and Sennikov S (2026) Advances in immunotherapy for HPV-associated malignancies: emerging strategies and clinical progress. Front. Immunol. 17:1897025. doi: 10.3389/fimmu.2026.1897025 The author(s) declared that financial support was received for this work and/or its publication. This research was funded by the Ministry of Higher Education and Science, State Assignment No.124112200103-3.

PY - 2026/9/16

Y1 - 2026/9/16

N2 - 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.

AB - 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.

KW - E6 and E7

KW - Engineered TCR T cells

KW - HPV

KW - human papillomavirus

KW - immune response

KW - therapeutic vaccine

UR - https://www.scopus.com/pages/publications/105052386543

UR - https://www.mendeley.com/catalogue/d3899166-72bd-3417-be8a-59950a543fc3/

U2 - 10.3389/fimmu.2026.1897025

DO - 10.3389/fimmu.2026.1897025

M3 - Article

C2 - 42819744

VL - 17

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 1897025

ER -