Extracellular Vesicles in Diffuse Midline Glioma: Emerging Mediators of Radiation Response and Therapeutic Resistance

DMG, including DIPG, is a highly aggressive pediatric brain tumor with dismal clinical outcomes. Radiotherapy remains the cornerstone of treatment, yet responses are transient and resistance is nearly universal. Emerging evidence indicates that EVs are key mediators of radiation response, facilitating intercellular communication and the propagation of radioresistant phenotypes within the tumor microenvironment. EVs carry diverse molecular cargo, including RNAs, proteins, and lipids, that can dynamically influence tumor behavior and treatment response. In this review, we focus on the role of EVs in shaping radiation response in DMG, while also examining their broader functions in tumor biology, biomarker development, and therapeutic delivery. We summarize evidence for EV-mediated regulation of tumor growth, invasion, microenvironmental interactions, and immune modulation. We further discuss the potential of EVs as minimally invasive biomarkers for liquid biopsy, highlighting both their advantages and current limitations relative to circulating tumor DNA (ctDNA) approaches. In addition, we review emerging strategies utilizing EVs as therapeutic delivery platforms capable of crossing the blood-brain barrier (BBB) and delivering small molecules and nucleic acid-based therapies. Finally, we explore the role of EVs in modulating radiation response, including their contribution to radioresistance and their potential as biomarkers of treatment efficacy. Although EV-based approaches hold significant promise in DMG, challenges related to standardization, specificity, and clinical validation remain. Continued investigation into EV biology and translational applications may provide new opportunities for improving diagnosis, monitoring, and treatment of this devastating disease.