Redefining head and neck cancer treatment with targeted therapy: Current landscape and emerging directions

Background: This comprehensive review discusses the current role of targeted therapies in head and neck squamous cell carcinoma, with a focus on known resistance mechanisms, recent combination strategies, and the direction of personalised treatment. Main Text: We performed a literature search between March and July 2025 across PubMed, Scopus, and Web of Science. The search focused on both MeSH terms and free-text keywords, including “Head and Neck Neoplasms,” “EGFR inhibition,” “Immune Checkpoint Inhibitors,” and “Combination Therapy.” Clinical trials, original research articles, and major reviews relevant to the scope of this review were included, with no restriction on publication year, resulting in a comprehensive synthesis of the available evidence. Cetuximab remains the only epidermal growth factor receptor targeting drug formally approved for head and neck squamous cell carcinoma, though its benefits are limited to specific patient groups. Immunotherapies like pembrolizumab and nivolumab demonstrate meaningful survival benefits in recurrent and metastatic settings, and their application is expanding into earlier disease stages. Combination strategies, including EGFR and programmed cell death protein 1 blockade, have shown promising activity. Consequently, dual-target regimens and adaptive strategies are attracting increasing attention. Liquid biopsy and biomarker-guided treatment selection are under active investigation to refine the personalisation of therapy. Conclusion: The management of head and neck squamous cell carcinoma is shifting toward more personalised and adaptive strategies that combine targeted therapies with immunomodulation. The integration of molecular profiling, real-time monitoring, and smarter trial designs will likely play a key role in improving the precision and durability of treatment responses.