Pediatric central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children. Development of more effective therapies for pediatric CNS tumors has been slow, underscoring an urgent need for novel and innovative approaches.

This review summarizes current pediatric clinical trials of oncolytic viruses for pediatric brain tumors including high-grade glioma (HGG), diffuse midline glioma (DMG), medulloblastoma (MDB), atypical teratoid rhabdoid tumors (ATRT), and other high-grade tumors, while highlighting limitations of early-phase data, exploratory biomarkers, imaging challenges, pseudoprogression, and future directions.

Key platforms include HSV-based agents (HSV1716, G207, and M032); adenoviral vectors (DNX2401, Ad-TD-nsIL12, and ICOVIR-5); MV-NIS (measles virus); PVS-RIPO (poliovirus); and Reolysin (reovirus). We review trial status, innovations in viral engineering and delivery, combinatorial strategies and translational challenges to establish oncolytic virotherapy as part of the future standard care for pediatric brain tumors.