髓母细胞瘤（MB）是儿童中最常见的脑癌。已确定甲基溴的四个亚类；其中，第 3 组转移性最强。与其他群体相比，其遗传学和生物学仍不太清楚，而且预后较差，有效的治疗方法很少。已知肿瘤缺氧和由此产生的代谢对于肿瘤的生长和存活很重要，但迄今为止，在 MB 中仅进行了很少的探索。在这里，我们表明，第 3 组 MB 肿瘤不依赖于经典转录因子缺氧诱导因子-1α (HIF-1α) 来对缺氧产生适应性反应。我们发现 HIF-1α 要么通过翻译后甲基化而失活，从而阻止其核定位（特别是在第 3 组 MB 中），要么通过低表达来阻止 HIF 靶基因的调节。引人注目的是，我们发现 HIF-2 取代了 HIF-1 在细胞核中的作用，并促进缺氧依赖性合成代谢途径的激活。在第 3 组 MB 细胞中，HIF-1 被排除在细胞核之外，增强了对 HIF-2 转录作用的依赖，使其成为潜在抗癌策略的可行靶点。通过将 HIF-2α 的药理抑制与使用二甲双胍（一种线粒体复合物 I 抑制剂来阻断呼吸）相结合，我们有效诱导了第 3 组 MB 细胞死亡，超过了在非第 3 组 MB 细胞中观察到的效果。总体而言，MB 细胞（而非正常细胞）对 HIF-2 介导的合成代谢代谢的独特依赖性为治疗 3 组 MB 患者提供了一个有吸引力的治疗机会，且毒性最小。

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.