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.