Cancer metastasis mediated by circadian rhythm disruption: Molecular mechanisms to clinical significance and implications

Circadian rhythm, a biological clock-regulated physiological phenomenon with a periodicity of approximately 24 h, is controlled by multiple core molecules, including BMAL1, CLOCK, PERs, and CRYs. Multiple lines of evidence demonstrates that circadian rhythm disruption can influence the metastatic cascade by modulating epithelial-mesenchymal transition, cancer stem cells, circulating tumor cells, the tumor microenvironment, and immune surveillance. Mechanistically, clock dysregulation drives extracellular matrix remodeling and alters matrix stiffness, fostering a pro-metastatic niche. It also disrupts immune homeostasis by inducing T cell exhaustion, promoting NK cell senescence, and reprogramming macrophage polarization toward tumor-supportive phenotypes. Therapeutically, targeting core circadian molecules and implementing chronotherapy have shown significant clinical potential. This review highlights the role of circadian rhythm disruption in promoting various stages of the metastatic cascade across cancers and explores the therapeutic potential of circadian-targeted agents and chronotherapy in controlling cancer metastasis. By synthesizing current evidence, we propose a novel conceptual framework that positions circadian rhythm disruption as a temporal gatekeeper of metastatic plasticity, offering a pan-cancer unifying model and new insights into the development of chronotherapeutic strategies aimed at controlling metastasis.