Cyclic GMP–AMP (cGAMP) is a second messenger that activates the stimulator of interferon genes (STING) innate immune pathway to induce the expression of type I IFNs and other cytokines. Pharmacologic activation of STING is considered a potent therapeutic strategy in cancer. In this study, we used a cell-based phenotypic screen and identified podophyllotoxin (podofilox), a microtubule destabilizer, as a robust enhancer of the cGAMP–STING signaling pathway. We found that podofilox enhanced the cGAMP-mediated immune response by increasing STING-containing membrane puncta and the extent of STING oligomerization. Furthermore, podofilox changed the trafficking pattern of STING and delayed trafficking-mediated STING degradation. Importantly, the combination of cGAMP and podofilox had profound antitumor effects on mice by activating the immune response through host STING signaling. Together, these data provide insights into the regulation of cGAMP–STING pathway activation and demonstrate what we believe to be a novel approach for modulating this pathway and thereby promoting antitumor immunity.

中文翻译：

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发现 Podofilox 作为具有抗肿瘤活性的有效 cGAMP-STING 信号增强剂

环 GMP-AMP (cGAMP) 是第二信使，可激活干扰素基因刺激剂 (STING) 先天免疫途径，诱导 I 型干扰素和其他细胞因子的表达。STING 的药理学激活被认为是癌症的有效治疗策略。在这项研究中，我们使用基于细胞的表型筛选并鉴定了鬼臼毒素（podofilox），一种微管去稳定剂，作为 cGAMP-STING 信号通路的强大增强剂。我们发现 Podofilox 通过增加含有 STING 的膜点和 STING 寡聚化程度来增强 cGAMP 介导的免疫反应。此外，podofilox 改变了 STING 的运输模式并延迟了运输介导的 STING 降解。重要的，cGAMP 和 Podofilox 的组合通过宿主 STING 信号激活免疫反应，对小鼠产生深远的抗肿瘤作用。总之，这些数据提供了对 cGAMP-STING 通路激活调节的见解，并证明了我们认为是调节该通路从而促进抗肿瘤免疫的新方法。