Advances in preclinical models for pediatric diffuse intrinsic pontine glioma

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive brainstem tumors, representing the leading cause of pediatric cancer-related mortality despite their rarity. DIPGs are predominantly characterized by the H3K27M mutation, which drives tumorigenesis through epigenomic reprogramming and dysregulated gene expression. A major barrier to therapeutic advancement has been the scarcity of representative preclinical models, historically limited by the rarity of tumor tissue samples. Recent advancements in biopsy safety and model development have accelerated progress in understanding DIPG biology and developing novel therapies. While current murine models offer valuable insights, they often fail to replicate the tumor's genetic and microenvironmental complexity fully. Non-murine models offer cost-effective platforms but are limited by anatomical and immunological differences that reduce their relevance to human DIPG. This review highlights advances and limitations in DIPG models, emphasizing the need for integrative approaches using multiple systems to validate therapies, as no single model can fully capture the disease's complexity. Addressing these gaps could lead to the development of novel treatments for DIPG.