Extracellular vesicles in head and neck cancer: mediators of oncogenesis, immune evasion, and therapy resistance

Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy due to its intratumoral heterogeneity, aggressive progression, and resistance to multimodal treatment. Extracellular vesicles (EVs)—including exosomes and microvesicles—have gained attention as active contributors to these phenotypes by mediating intercellular signaling and molecular cargo transfer. HNSCC-derived EVs carry oncogenic and drug resistance proteins, along with microRNAs that promote immune evasion and EMT. Enrichment of microRNAs including miR-21, miR-214, and miR-221/222 within EVs supports angiogenesis, apoptosis evasion, and immune suppression. EV-associated PD-L1 impairs antigen presentation and T cell activity, contributing to resistance to checkpoint blockade. Additionally, EVs promote epithelial-to-mesenchymal transition and extracellular matrix remodeling, facilitating invasion and pre-metastatic niche formation. Through modulation of T cell function, macrophage polarization, and stromal recruitment, EVs help establish an immune-tolerant microenvironment. This review synthesizes current knowledge on the mechanistic roles of EVs in HNSCC and discusses their potential as diagnostic biomarkers and therapeutic targets.