RNA sensing induced by chromosome missegregation augments anti-tumor immunity. Sasaki et al.

Viral mimicry triggered by endogenous double-stranded RNA (dsRNA) stimulates innate and adaptive immune responses. However, the mechanisms that regulate dsRNA-forming transcripts and the contexts in which these transcripts accumulate in the cytoplasm during cancer therapy remain incompletely understood. In this study, we demonstrate that pharmacologic induction of micronuclei leads to significant accumulation of dsRNA in cancer cells, which activates MAVS-mediated dsRNA sensing in conjunction with the cGAS/STING pathway. These data, including western blotting, immunofluorescence, and immunocytochemistry images, reveal that pulsed treatment with a monopolar spindle 1 (MPS1) kinase inhibitor—an agent that effectively induces micronuclei formation—triggers cytoplasmic dsRNA sensing, promotes type I interferon signaling in vitro, and enhances anti-tumor immunity mediated by type I interferon signaling in vivo. These findings uncover a novel role of the dsRNA-sensing pathway in augmenting the anti-tumor efficacy of drugs that induce genomic instability and micronuclei formation, thereby enhancing cancer immunogenicity.

由内源性双链RNA（dsRNA）触发的病毒模拟感染激活了先天性和适应性免疫反应。然而，调节dsRNA形成转录本及其在癌症治疗过程中在细胞质中积累的上下文机制尚不完全明了。在本研究中，我们证明了药理诱导的微核形成导致癌细胞中dsRNA的显著积累，这激活了MAVS介导的dsRNA感知与cGAS/STING途径的协同作用。这些数据，包括蛋白质印迹、免疫荧光和免疫细胞化学图像，揭示了脉冲式治疗使用单极纺锤体1（MPS1）激酶抑制剂——一种有效诱导微核形成的药物——触发了细胞质中dsRNA的感知，在体外促进了I型干扰素的信号传导，并在体内增强了由I型干扰素信号传导介导的抗肿瘤免疫。这些发现揭示了dsRNA感知途径在增强诱导基因组不稳定性和微核形成的药物的抗肿瘤疗效中的新型作用，从而增强了癌症的免疫原性。