Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module should help to maximize the efficacy of radiotherapy. In the current study, we report that inhibitors of the DNA damage response kinase ATR can significantly potentiate ionizing radiation‐induced innate immune responses. Using a series of mammalian knockout cell lines, we demonstrate that, surprisingly, both the cGAS/STING‐dependent DNA‐sensing pathway and the MAVS‐dependent RNA‐sensing pathway are responsible for type I interferon signaling induced by ionizing radiation in the presence or absence of ATR inhibitors. The relative contributions of these two pathways in type I interferon signaling depend on cell type and/or genetic background. We propose that DNA damage‐elicited double‐strand DNA breaks releases DNA fragments, which may either activate the cGAS/STING‐dependent pathway or—especially in the case of AT‐rich DNA sequences—be transcribed and initiate MAVS‐dependent RNA sensing and signaling. Together, our results suggest the involvement of two distinct pathways in type I interferon signaling upon DNA damage. Moreover, radiation plus ATR inhibition may be a promising new combination therapy against cancer.

中文翻译：

---

ATR抑制通过细胞溶质核酸传感途径增强电离辐射诱导的干扰素反应。

对电离辐射如何诱导I型干扰素信号传导以及如何放大该信号传导模块的机械理解应有助于最大化放疗的功效。在当前的研究中，我们报道了DNA损伤反应激酶ATR的抑制剂可以显着增强电离辐射诱导的先天免疫反应。令人惊讶的是，使用一系列哺乳动物基因敲除细胞系，我们证明了cGAS / STING依赖的DNA传感途径和MAVS依赖的RNA传感途径均是由存在或不存在的电离辐射诱导的I型干扰素信号负责的。缺少ATR抑制剂。这两种途径在I型干扰素信号传导中的相对贡献取决于细胞类型和/或遗传背景。我们建议，DNA损伤引起的双链DNA断裂释放DNA片段，该片段可能激活cGAS / STING依赖的途径，或者尤其是富含AT的DNA序列被转录并启动依赖MAVS的RNA感应，信号。总之，我们的结果表明DNA损伤时I型干扰素信号传导涉及两个不同的途径。此外，辐射加ATR抑制可能是一种有前途的抗癌新疗法。