Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for approximately 25% of all pediatric brain tumors. Among medulloblastoma, group 3 medulloblastoma (MBG3) carries the poorest prognosis, with a 5-year overall survival of less than 60%. The current standard of care consists of maximal surgical resection followed by radiation therapy and adjuvant chemotherapy. However, despite this aggressive treatment approach, approximately 30% of MBG3 patients experience tumor relapse. These recurrent tumors are often metastatic and resistant to therapy, underscoring the critical need to understand the mechanisms underlying therapy resistance in MBG3 cells. To investigate this, we examined cellular metabolic adaptations in response to the stress induced by chemoradiotherapy (CRT). Our findings revealed a distinct upregulation of mitochondrial tricarboxylic acid (TCA) cycle enzymes in MBG3 cells following CRT exposure. However, this increase was not accompanied by a corresponding rise in mitochondrial activity. Instead, we observed that these enzymes were selectively upregulated within the nuclear compartment of CRT-treated (CRT-T) cells. The presence of TCA cycle activity in the nucleus suggests a potential role for metabolite-driven epigenetic modifications in response to CRT. To explore this, we examined key histone modification sites commonly altered in MBG3: histone H3 lysine 27 (H3K27), histone H3 lysine 9 (H3K9), and histone H3 lysine 4 (H3K4). Our analysis confirmed significant changes in both acetylation and methylation, indicating that CRT promotes a transcriptionally active state that may enable MBG3 cells to adapt by upregulating genes associated with stress response and survival. Moving forward, identifying these transcriptional changes will provide critical insights into the mechanisms driving tumor relapse in MBG3, potentially uncovering novel therapeutic targets to overcome treatment resistance.