Microtubule-targeting agents (MTAs), including both microtubule stabilizers and destabilizers are highly effective chemotherapeutic drugs used in the treatment of solid tumors and hematologic malignancies. In addition to the shared ability of all MTAs to block cell cycle progression, growing evidence shows that different agents of this class can also have mechanistically distinct effects on nonmitotic microtubule-dependent cellular processes, including cellular signaling and transport. Herein, we test the biologic hypothesis that MTAs used in the treatment of triple-negative breast cancer (TNBC) can differentially affect innate immune signaling pathways independent of their antimitotic effects. Our data demonstrate that the microtubule destabilizer eribulin, but not the microtubule stabilizer paclitaxel, induces cGAS-STING–dependent expression of interferon-β in both myeloid and TNBC cells. Activation of the cGAS-STING pathway by eribulin was further found to be mediated by the accumulation of cytoplasmic mitochondrial DNA. Together, these findings provide mechanistic insight into how eribulin can induce innate immune signaling independent of its antimitotic or cytotoxic effects.

中文翻译：

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艾日布林通过线粒体 DNA 的细胞质积累激活 cGAS-STING 通路

微管靶向剂 (MTA)，包括微管稳定剂和去稳定剂，是用于治疗实体瘤和血液系统恶性肿瘤的高效化疗药物。除了所有 MTA 共同阻断细胞周期进程的能力外，越来越多的证据表明，这类不同的药物也可以对非有丝分裂微管依赖性细胞过程产生不同的机制影响，包括细胞信号传导和转运。在这里，我们检验了用于治疗三阴性乳腺癌 (TNBC) 的 MTA 可以不同地影响先天免疫信号通路的生物学假设，而与它们的抗有丝分裂作用无关。我们的数据表明，微管去稳定剂艾日布林，而不是微管稳定剂紫杉醇，β在骨髓和 TNBC 细胞中。进一步发现艾日布林对 cGAS-STING 途径的激活是由细胞质线粒体 DNA 的积累介导的。总之，这些发现提供了对艾日布林如何诱导先天免疫信号传导而不受其抗有丝分裂或细胞毒性作用的机制洞察。