Therapeutic HPV vaccines for PD-1 blockade–resistant HPV-positive head and neck squamous cell carcinoma: mechanistic rationale, clinical limitations, and biomarker-guided combinations

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that continues to present substantial therapeutic challenges despite decades of research. Immune checkpoint blockade agents targeting the programmed death receptor-1 (PD-1) axis have emerged as a frontline therapeutic modality for patients with recurrent/metastatic disease. However, suboptimal objective response rates and pervasive inherent and acquired resistance mechanisms significantly limit clinical efficacy. Notably, the escalating incidence of human papillomavirus (HPV)-driven HNSCC, particularly oropharyngeal squamous cell carcinoma (OPSCC), has necessitated novel treatment paradigms. The HPV-encoded oncoviral antigens represent optimal targets for precision immunotherapeutic interventions. Here, we summarize the multifactorial mechanisms underlying resistance to PD-1 blockade in HNSCC and discuss how therapeutic HPV vaccines may restore antitumor immune responses by remodeling the tumor immune microenvironment (TIME) and expanding virus-specific cytotoxic T lymphocytes. These findings support the biological rationale for combining therapeutic HPV vaccines with PD-1/PD-L1 blockade; however, this strategy should still be regarded as investigational because clinical benefit has not been consistently demonstrated in randomized studies. In addition, we review recent preclinical and translational advances, compare major vaccine delivery platforms, and discuss future research directions and challenges in this evolving field. Finally, we advance a working hypothesis that therapeutic efficacy is contingent upon three biological prerequisites—intact MHC-I antigen presentation, baseline PD-L1 expression, and the absence of dominant non-PD-1 immunosuppressive barriers—and discuss the implications of this precision-enrichment framework for future trial design.