The circadian-melatonin axis in breast cancer metastasis: molecular mechanisms, organ-specific metastatic niches, and therapeutic opportunities.

Breast cancer metastasis remains the leading cause of disease-related mortality despite major advances in systemic therapy. Increasing evidence indicates that the circadian-melatonin axis may influence metastatic progression by coordinating endocrine signaling, metabolism, immune responses, and tumor cell plasticity. In this review, we summarize current epidemiological, mechanistic, and translational evidence linking circadian disruption and melatonin to breast cancer metastasis. We discuss how core circadian clock genes and melatonin signaling may influence epithelial-mesenchymal transition, cancer stemness, circulating tumor cell dissemination, tumor metabolism, and immune remodeling. We further highlight the emerging potential roles of melatonin in shaping adipocyte-tumor crosstalk and organ-specific metastatic niches, including bone, lung, liver, and brain, where tissue-specific interactions may influence metastatic colonization. Finally, we discuss the clinical potential of circadian chronotherapy, adjuvant melatonin, and circadian biomarker-guided precision medicine. Although substantial experimental evidence supports the anti-metastatic properties of the circadian-melatonin axis, clinical translation remains limited by context-dependent biological effects and the lack of chronobiology-informed trials. Future studies integrating circadian biomarkers with optimized treatment timing and modern systemic therapies may facilitate precision strategies for preventing and treating metastatic breast cancer.