Immunotherapeutic strategies in HPV-positive and HPV-negative recurrent/metastatic oropharyngeal squamous cell carcinoma: from PD-1 blockade to EGFR-directed bispecifics and therapeutic HPV vaccines

Oropharyngeal squamous cell carcinoma (OPSCC) comprises two biologically distinct entities, HPV-positive and HPV-negative disease, which differ in etiology, immune microenvironment, molecular drivers, and clinical behavior. This narrative review summarizes current evidence on immunotherapeutic strategies in OPSCC, focusing on subtype-specific biological rationale and emerging treatment approaches. A literature search of PubMed/MEDLINE, Embase, Cochrane Library, ClinicalTrials.gov, and major oncology meeting abstracts was conducted for studies published from January 2000 to February 2026. PD-1/PD-L1 inhibitors represent the current standard of care in recurrent/metastatic disease, with HPV-positive tumors generally showing more favorable outcomes, likely reflecting a more inflamed and antigen-rich tumor microenvironment. However, HPV status remains primarily a prognostic rather than a validated predictive biomarker for checkpoint inhibitor benefit. In contrast, HPV-negative OPSCC is more frequently characterized by immune exclusion, EGFR dependence, hypoxia, and activation of MET/HGF and TGF-β pathways, supporting the development of EGFR-centered and bifunctional strategies to overcome resistance. Emerging agents such as ficerafusp alfa, petosemtamab, and amivantamab have demonstrated promising early clinical activity, particularly in biomarker-enriched or post-immunotherapy settings. In HPV-positive disease, therapeutic vaccines targeting E6/E7 oncoproteins have shown encouraging immunogenicity and preliminary antitumor activity, especially when combined with PD-1 blockade. Overall, the immunotherapeutic landscape of OPSCC is evolving toward a biomarker-driven framework integrating viral status, immune contexture and pathway activation to enable more precise and personalized treatment strategies. • HPV+ and HPV− OPSCC show distinct immune vulnerabilities. • HPV status is prognostic, not a validated predictive ICI biomarker. • EGFR-driven and TGF-β pathways sustain resistance in HPV− disease. • Bispecific and bifunctional agents show promising early activity. • Therapeutic HPV vaccines may enhance PD-1 blockade efficacy