Extracellular Vesicles in Head and Neck Cancer: Mediators of Oncogenesis, Immune Evasion, and Therapy Resistance

Jillian Dean¹Tobias Niederegger²Cosima C. Hoch³Bhagvat Maheta⁴Barbara Wollenberg³Friedrich Mrosk²Maximilian Richter²Max Heiland²Jan Voss²Adriana C. Panayi²Steffen Koerdt²Leonard Knoedler^2,5*

• ¹University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA, Pittsburgh, United States
• ²Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Oral and Maxillofacial Surgery, Berlin, Germany, Berlin, Germany
• ³Department of Otolaryngology, Head and Neck Surgery, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany, Munich, Germany
• ⁴California Northstate University, College of Medicine, Elk Grove, CA, USA, Elk Grove, United States
• ⁵Department of Oral and Maxillofacial Surgery, Charité University Hospital Berlin, Berlin, Germany

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.