Pharmacological Targeting of Angiogenesis in Head and Neck Cancer: Molecular Mechanisms and Emerging Therapeutic Strategies

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive and heterogeneous malignancies worldwide, characterized by high rates of locoregional recurrence, metastatic dissemination, and therapeutic resistance. Angiogenesis plays a central role in tumor progression by supporting vascular remodeling, hypoxia adaptation, invasion, immune evasion, and metastatic spread. In HNSCC, angiogenic activation is regulated through complex interactions involving hypoxia-inducible factors, vascular endothelial growth factor (VEGF) signaling, stromal remodeling, inflammatory pathways, and epigenetic mechanisms within the tumor microenvironment. Recent evidence has also highlighted the role of non-coding RNAs, particularly microRNAs, and exosome-mediated communication in modulating angiogenic and immune-related signaling pathways. Although antiangiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated biological activity in HNSCC, their clinical efficacy remains limited by tumor heterogeneity, adaptive resistance mechanisms, toxicity, and the lack of validated predictive biomarkers. Several emerging therapeutic strategies are under preclinical or early clinical investigation in HNSCC, including miRNA-based approaches, nanoparticle-assisted delivery systems, vascular normalization concepts, and combinations with immune checkpoint inhibitors; however, robust clinical evidence for most of these strategies remains limited, and their translation to routine practice requires further validation. This review provides a comprehensive overview of the molecular mechanisms regulating angiogenesis in HNSCC and critically discusses current and emerging pharmacological strategies targeting these pathways. Particular emphasis is placed on VEGF/VEGFR signaling, the integration of miRNA and exosome biology, resistance mechanisms, and translational perspectives for biomarker-guided personalized therapy. The novelty of this review lies in the systematic integration of miRNA- and exosome-mediated angiogenic regulation, therapeutic resistance pathways, and precision medicine strategies into a unified pharmacological framework, addressing gaps not fully covered by prior reviews focused primarily on VEGF-targeted agents.