放射治疗 (RT) 通常用于消除神经胶质瘤手术切除后残留的肿瘤细胞。然而，肿瘤复发很普遍，凸显了开发治疗策略以增强神经胶质瘤放疗疗效的医疗需求尚未得到满足。关注目前批准的已知可穿过血脑屏障的药物的放射增敏潜力可以促进快速临床转化。在这里，我们评估了儿茶酚邻甲基转移酶 (COMT) 在神经胶质瘤治疗中的作用，COMT 是一种降解儿茶酚胺的关键酶，也是帕金森病的药物靶点。 TCGA 数据分析显示，与正常脑组织相比，低级别胶质瘤和胶质母细胞瘤中 COMT 表达水平显着升高。通过基因敲除或 FDA 批准的 COMT 抑制剂对 COMT 的抑制显着使神经胶质瘤细胞在体外和体内对 RT 敏感。从机制上讲，神经胶质瘤细胞中的 COMT 抑制导致线粒体功能障碍，并增加线粒体 RNA 释放到细胞质中，激活细胞抗病毒双链 RNA 传感途径和 I 型干扰素 (IFN) 反应。升高的 I 型干扰素刺激小胶质细胞的吞噬能力，​​增强 RT 功效。鉴于 COMT 抑制剂长期以来的安全性记录，这些发现为在神经胶质瘤患者中评估它们与 RT 的结合提供了坚实的理由。

Radiotherapy (RT) is commonly used to try to eliminate any remaining tumor cells following surgical resection of glioma. However, tumor recurrence is prevalent, highlighting the unmet medical need to develop therapeutic strategies to enhance the efficacy of RT in glioma. Focusing on the radiosensitizing potential of currently approved drugs known to cross the blood-brain barrier can facilitate rapid clinical translation. Here, we assessed the role of catechol-o-methyltransferase (COMT), a key enzyme to degrade catecholamines and a drug target for Parkinson's disease, in glioma treatment. Analysis of TCGA data showed significantly higher COMT expression levels in both low-grade glioma and glioblastoma compared to normal brain tissues. Inhibition of COMT by genetic knockout or FDA-approved COMT inhibitors significantly sensitized glioma cells to RT in vitro and in vivo. Mechanistically, COMT inhibition in glioma cells led to mitochondria dysfunction and increased mitochondrial RNA release into the cytoplasm, activating the cellular antiviral double-stranded RNA sensing pathway and type I interferon (IFN) response. Elevated type I IFNs stimulated the phagocytic capacity of microglial cells, enhancing RT efficacy. Given the long-established safety record of the COMT inhibitors, these findings provide a solid rationale to evaluate them in combination with RT in glioma patients.