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While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous inflammatory response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose envelopes frequently rupture exposing their DNA content to the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-kB signaling. Genetic suppression of CIN significantly delays metastasis in transplantable tumor models, whereas inducing chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. In contrast to primary tumors, human and mouse metastases strongly select for CIN, in part, due to its ability to enrich for metastasis-initiating mesenchymal subpopulations, offering an opportunity to target chromosome segregation errors for therapeutic benefit. Overall design: To determine whether CIN is causally involved in metastasis, we devised a genetic approach to alter the rate of chromosome missegregation in transplantable tumor models of human TNBC (MDA-MB-231) cont: Control sample. Part of the CIN-medium group. Ka Overexpression of Kif2a, which does not affect the number of chromosome segregation errors during anaphase and serves as an additional control. Part of the CIN-medium group. Kb Overexpression of Kif2b, which leads to suppressed chromosome segregation errors during anaphase. Part of the CIN-low group. MK Overexpression of MCAK which leads to suppressed chromosome segregation errors during anaphase. Part of the CIN-low group. MKH Overexpression of dominant-negative form of MCAK, leading to increased number of chromosome segregation errors during anaphase. Part of the CIN-high group.xref:PubMed:29342134ENAfalseHomo sapiensChromosomal instability promotes metastasis through a cytosolic DNA response2025-09-242018-03-01PRJNA384217GSE98183960629342134