Many cancer cells exhibit a “chromosome instability (CIN)” phenotype, where chromosomes frequently fail to equally distribute to daughter cells. How chromosome missegregation contributes to tumorigenesis remains unclear. In addition, anti-microtubule drugs (e.g. taxol), which cause mitotic arrest and chromosome missegregation, are commonly used to treat breast and other cancers, but their underlining mechanisms are not established. We showed that the innate immune system, which normally responds to pathogenic DNAs, senses aberrant mitosis and affects cell fates. While cGAS, the major cytoplasmic DNA sensor of the innate immune system, is activated by pathogenic DNA and stimulates inflammation, we demonstrated that cGAS cannot be activated during normal mitosis. In fact, cGAS binds to the mitotic chromosomes. We show that nucleosomes act as a competitive inhibitor for DNA-dependent activation of cGAS; this prevents cGAS being activated by chromosomal DNA. However, when cells are arrested in mitosis upon treatment with taxol, cGAS is slowly activated to promote apoptosis.