# CINs of the cytoplasm: dissecting dsRNA signaling in chromosomal instability

## TL;DR

Chromosomal instability in cancer cells leads to the release of RNA that activates the immune system, offering new insights into tumor-immune interactions.

## Contribution

The study reveals that chromosomal instability generates immunogenic RNA, activating MAVS-dependent immune responses independently of DNA sensing.

## Key findings

- Micronuclei rupture and release double-stranded RNA, triggering MAVS-dependent interferon signaling.
- Aberrant transcription near interferon-stimulated genes amplifies immune activation through a feedforward loop.
- MPS1 inhibition-induced CIN activates MHC Class I expression and immune cell recruitment via MAVS signaling.

## Abstract

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.

Micronuclei, formed during cell division in chromosomal instability settings, rupture and lead to the accumulation of immunogenic double‐stranded RNA in the cytoplasm, activating MAVS‐dependent interferon signaling and innate antitumor immunity. Aberrant transcription from interferon‐stimulated genes further amplifies this response through a feedforward loop, establishing RNA sensing as a distinct axis of CIN‐induced inflammation.