Metastasis in biological time.

Metastasis is the leading cause of cancer-related death, yet it is still interpreted largely through genetic, spatial, and microenvironmental models that treat the host as temporally uniform. Emerging evidence challenges this view by showing that metastatic progression unfolds within a hierarchically organized circadian system in which tumour cells, vascular interfaces, immune compartments, and distant organs operate in biological time. In this review, we examine how circadian regulation shapes multiple stages of the metastatic cascade, including tumour metastatic competence, circulating tumour cell release, vascular trafficking, immune-mediated seeding, niche permissiveness, colonization, and metastatic outgrowth. We discuss how tumour-intrinsic clocks influence invasive and secretory programmes, how endothelial and stromal rhythms create time-dependent windows of tissue access, and how circadian immune dynamics determine whether disseminated tumour cells are eliminated or licensed for persistence. We further highlight the role of systemic zeitgebers, including light-dark cycles, feeding-fasting rhythms, glucocorticoids, autonomic signalling, and body temperature, in coordinating or disrupting temporal alignment across metastatic compartments. Together, these observations support a conceptual shift: metastasis should be understood not only as a disease of space and state, but also as a disease of biological time. This framework may help explain metastatic heterogeneity and inform future precision oncology strategies.