The emerging landscape for next-generation HNSCC treatment.

Head and neck squamous cell carcinoma (HNSCC) is a biologically complex malignancy in which durable responses to standard multimodal therapies, targeted therapies, and immune checkpoint inhibitors remain limited. Therapeutic resistance arises from interconnected oncogenic signaling, tumor plasticity, heterogeneity, and immune evasion, which enable tumors to bypass inhibition of individual pathways. These mechanisms also differ across biologically distinct HNSCC subsets, including human papillomavirus (HPV)-positive and HPV-negative disease. Emerging therapeutic platforms in preclinical and clinical development, including targeted protein degraders, engineered antibodies, cellular and vaccine-based immunotherapies, photoimmunotherapy, and epigenetic modulators, provide new opportunities to target these interconnected vulnerabilities. In this review, we examine how these pharmacological strategies may overcome resistance in HNSCC and discuss their integration into biomarker-guided, mechanism-driven combination regimens.