Abstract Introduction Medulloblastoma (MB) is the most common malignant pediatric brain tumor and comprises molecularly distinct subgroups with pronounced differences in prognosis and therapy response. While radiotherapy remains a cornerstone of treatment, intrinsic radioresistance in high-risk subtypes such as MYC-amplified Group 3 and TP53-mutated SHH-MB significantly limits therapeutic success and contributes to long-term toxicity. Increasing evidence suggests that metabolic plasticity critically influences the radiation response, yet subtype-specific metabolic adaptations remain insufficiently characterized. Methods Representative medulloblastoma cell models of SHH and Group 3/4 subtypes were subjected to radiobiological and functional metabolic characterization following irradiation. Short- and long-term cellular responses were assessed alongside radiation-induced alterations in mitochondrial function and cellular energy metabolism. Translational validation in preclinical models, including the chicken chorioallantoic membrane (CAM) model, is planned as a next step. Results Initial analyses revealed pronounced subtype-specific differences in radiation response, with SHH-MB models exhibiting enhanced proliferative capacity and metabolic adaptability compared to Group 3/4 models. Radiation exposure induced distinct metabolic responses, suggesting differential reliance on mitochondrial function and energy production pathways across MB subtypes. Collectively, these data support a model in which mitochondrial adaptability and energy metabolism are associated with subgroup-specific radiation response phenotypes. Conclusion Our data highlight fundamental differences in radiation-associated metabolic adaptations between medulloblastoma subgroups. Defining subgroup-specific metabolic dependencies and their coupling to irradiation-induced stress responses may support the rational development of combination strategies to improve therapeutic efficacy while potentially reducing treatment-associated toxicity. Ongoing studies aim to further delineate actionable metabolic vulnerabilities in high-risk medulloblastoma. Acknowledgement Supported by the German Federal Ministry of Research, Technology and Space (BMFTR), grant 02NUK090B and 02NUK090A.
Mallick et al. (Tue,) studied this question.