Hijacking Developmental Immunity: Inflammation and Immune Dysregulation in Pediatric Brain Tumors

Pediatric brain tumors (PBTs) remain a leading cause of cancer-related mortality in children, underscoring the need for more effective therapeutic strategies. These tumors arise from disrupted neurodevelopmental programs and evolve within a developmentally constrained immune landscape that is tolerogenic, epigenetically plastic, and susceptible to tumor-mediated co-option. Increasing evidence indicates that, besides molecular heterogeneity, the tumor immune microenvironment critically influences clinical outcomes. Despite its therapeutic promise, immunotherapy has yet to demonstrate consistent clinical benefit in most PBTs, highlighting the need for rational multimodal strategies guided by deeper understanding of tumor-immune interactions in the developing brain. To provide a comprehensive perspective on fetal immune ontogeny and its tumor-driven dysregulation we used medulloblastoma, pediatric gliomas, atypical teratoid/rhabdoid tumors, and ependymoma as representative entities. Drawing on insights from developmental neurobiology, tumor immunology, and emerging multi-omic studies, we outline how PBTs exploit physiological immune maturation programs to establish immune evasion, sustain chronic inflammation, and promote therapy resistance. We further discuss emerging multimodal immunotherapeutic strategies and next-generation CAR T-cell approaches currently under clinical investigation. In addition, we highlight therapeutic avenues such as targeting tumor-associated myeloid populations and key inflammatory regulators that may offer promising opportunities for future clinical translation. We believe this Review will help address current limitations in preclinical models, improve patient stratification and guide rational design of therapeutic strategies.