Circadian-driven transcriptional programs govern metastatic progression

Circadian rhythms orchestrate 24-h oscillations in gene expression to govern diverse physiologic functions. Mounting evidence suggests that circadian disruption, resulting from aberrant light exposure, shift work, or genetic mutations in core clock genes (e.g., BMAL1 and PER2), promotes tumorigenesis and progression by dysregulating proliferation, apoptosis, cell cycle progression, metabolic reprogramming, and senescence. Critically, the circadian clock exerts spatiotemporal control over the tumor microenvironment, a dynamic ecosystem central to metastatic efficiency. This review synthesizes emerging mechanisms underlying circadian regulation of tumor microenvironment (TME) components during the metastatic cascade: 1) extracellular matrix (ECM) dynamics. Circadian oscillation of matrix metalloproteinases remodels collagen alignment at invasive edges. 2) Stromal crosstalk. Rhythmic secretion of cytokine by cancer-associated fibroblasts or macrophages gates intravasation efficiency on circulating tumor cells. 3) Immune-extravasation axis. Diurnal variations in endothelial adhesion molecules (ICAM-1/VCAM-1) regulate CTC extravasation, synchronized with neutrophil infiltration peaks. In this review how circadian perturbations (e.g., jet lag-induced cortisol spikes or CRY1 knockout) alter cytokine networks (TGF-β/IL-6), hypoxia responses, and metabolic symbiosis within the TME were dissected. This work unveiled chronotherapeutic targets to disrupt metastasis timing by integrating recent single-cell RNA-seq and intravital imaging data. However, details regarding the molecular mechanisms underlying TME have not been established. We anticipate that upcoming research will deepen our comprehension of these complex interactions, facilitating the creation of novel strategies for cancer therapy.