Chromosome dynamics—including segregation fidelity, nuclear architecture, micronuclei formation, and chromothripsis—plays a central role in cancer evolution, intra-tumoral heterogeneity, and therapy resistance. Defective mitosis and subsequent chromosomal mis-segregation rapidly generate aneuploidy and structural rearrangements, accelerating tumor adaptation under selective pressures. Micronuclei serve as both a biomarker and a mechanistic driver of genomic chaos, often leading to catastrophic events such as chromothripsis. Moreover, the rupture of micronuclear envelopes can activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS- STING) innate immune pathway, further shaping the tumor microenvironment and response to immunotherapy. Advances in live-cell imaging, single-cell genomics, clustered regularly interspaced short palindromic repeats-based (CRISPR) functional screens, and 3D genome mapping have elucidated how chromosomal instability (CIN) shapes tumor evolution and provides targetable vulnerabilities. This review synthesizes current understanding of chromosome dynamics in cancer, integrating mechanistic insights with translational implications, and proposes strategies for exploiting these processes therapeutically.

Chromosomal instability (CIN), Micronuclei, Chromothripsis, cGAS–STING pathway, Tumor evolution, Aneuploidy