# Small Extracellular Vesicles From Radioresistant H3K27M‐Pediatric Diffuse Midline Glioma Cells Modulate Tumor Phenotypes and Radiation Response

## TL;DR

This study shows that extracellular vesicles from resistant glioma cells help other tumor cells survive radiation therapy by altering their DNA repair and metabolism.

## Contribution

The study reveals how radioresistant glioma-derived vesicles promote radiation resistance through metabolic and transcriptional reprogramming.

## Key findings

- RR-sEVs enhance DNA repair and survival in radiosensitive tumor cells after radiation.
- RR-sEVs carry proteins, miRNAs, and metabolites linked to glycolysis, oxidative phosphorylation, and DNA repair.
- sEV uptake alters gene expression and metabolic pathways in recipient tumor cells.

## Abstract

Pediatric diffuse midline gliomas with the Histone 3 lysine 27‐to‐methionine mutation (H3K27M‐pDMG) are aggressive brain tumors characterized by intrinsic resistance to radiation therapy, the current standard of care. These tumors exhibit significant intratumoral heterogeneity, with distinct subclonal populations likely contributing to therapy resistance. Emerging evidence suggests that small extracellular vesicles (sEV) mediate oncogenic signaling within glioma stem cell populations, yet their role under radiation‐induced stress remains poorly understood. In this study, we characterized sEV uptake dynamics among H3K27M‐pDMG tumor cells, identified key sEV surface proteins, and demonstrated that sEVs derived from radioresistant (RR) H3K27M‐pDMG cells confer radioprotective effects on radiosensitive tumor cells. Molecular profiling revealed that RR‐sEVs carry proteins, microRNAs (miRNAs) and metabolites associated with glycolysis, oxidative phosphorylation and DNA repair. Upon uptake, RR‐sEVs reprogrammed recipient cells by altering gene expression and metabolic pathways, and enhancing DNA repair and survival following radiation exposure. These findings provide insights into the role of sEV‐mediated intratumoral communication as a contributor to radiation resistance in H3K27M‐pDMG and suggest potential therapeutic strategies to disrupt this process and enhance radiation efficacy.

Radioresistant H3K27M‐pediatric diffuse midline glioma‐derived extracellular vesicles enhance DNA repair and trigger metabolic and transcriptional changes in radiosensitive tumor cells. These findings reveal vesicle‐mediated intratumoral communication as a driver of intrinsic radioresistance and suggest novel targets to disrupt therapy‐resistant signaling in this lethal pediatric brain tumor.