<scp>CIN</scp>s of the cytoplasm: dissecting ds<scp>RNA</scp> signaling in chromosomal instability

Chromosomal instability (CIN), a pervasive feature of cancer, promotes tumor evolution and inflammatory signaling, yet its influence on innate immune sensing remains incompletely understood. Ruptured micronuclei, a direct byproduct of CIN arising from missegregated chromosomes, expose out-of-context double-stranded DNA that engages the cGAS-STING pathway. In their recent study, Sasaki et al. show that micronuclei are also a source of immunogenic double-stranded RNA (dsRNA), triggering MAVS-dependent type I interferon responses independently of STING. The authors show that micronuclei undergo aberrant transcription, producing dsRNA from nonexonic, transcriptionally accessible loci, with many species localizing near interferon-stimulated genes. This work suggests a feedforward loop in which type I interferon signaling reinforces its own activation through transcriptional dysregulation. Using MPS1 inhibition to induce acute CIN, the authors show that MAVS signaling promotes MHC Class I expression and immune cell recruitment. These findings reposition CIN as a dual trigger of innate immunity through cytoplasmic DNA and RNA sensing. Future work should define how these pathways integrate in the context of chronic CIN and evaluate strategies to target DNA and RNA sensing in immune-edited tumors.