Infant Embryonal CNS Tumors: Molecular Insights and Treatment Considerations for Contemporary Pediatric Neuro‐Oncology

BACKGROUND: Embryonal tumors comprise the majority of malignant central nervous system (CNS) neoplasms diagnosed in children under 3 years of age. Compared with their counterparts in older children, these tumors exhibit distinct molecular biology and a more aggressive clinical phenotype, while their management is complicated by the heightened vulnerability of the developing brain to acute toxicity and long-term sequelae from surgery, chemotherapy, and radiotherapy. OBJECTIVES: To summarize the contemporary understanding of infant CNS embryonal tumors, including molecular classification, treatment paradigms, and emerging therapeutic strategies, and to outline a framework for molecularly driven, risk-adapted management. DESIGN AND METHODS: We performed a narrative review of published cooperative-group, consortium, and single-institution trials in medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), embryonal tumor with multilayered rosettes (ETMR), pineoblastoma, and other infant CNS embryonal entities, integrating findings with the 2021 WHO Classification of CNS Tumors and recent DNA methylation- and next-generation sequencing-based subclassifications. RESULTS: Molecular profiling has reshaped diagnosis and risk stratification across all infant embryonal entities, identifying clinically actionable subgroups (e.g., SHH-I/II in medulloblastoma; AT/RT-TYR, -SHH, -MYC; ETMR with C19MC or DICER1 alterations; pineoblastoma molecular subgroups). Multimodal regimens that delay or avoid craniospinal irradiation have achieved durable survival in favorable-risk SHH-activated medulloblastoma, while outcomes remain poor for Group 3 medulloblastoma, ETMR, pineoblastoma, and metastatic AT/RT. Investigational targeted and immunotherapeutic strategies, intraventricular methotrexate, proton-beam radiotherapy, and cerebrospinal fluid liquid biopsy are increasingly being incorporated into risk-adapted approaches. CONCLUSION: Molecularly driven, risk-adapted clinical trials and international collaborative registries are essential to advance care for infants with CNS embryonal tumors, with the dual goals of improving survival and reducing treatment-related neurodevelopmental morbidity.