Circadian rhythms in the tumor microenvironment: spatiotemporal immune regulation and chronotherapeutic opportunities

The tumor microenvironment (TME) is increasingly recognized as a temporally organized ecosystem rather than a static structural niche. Circadian rhythms, generated by transcriptional–translational feedback loops involving CLOCK, BMAL1, PER, CRY, REV-ERB, and ROR, coordinate systemic physiology and local cellular programs that are directly relevant to tumor initiation, progression, and therapeutic response. In this review, we summarized how circadian regulation shapes tumor rhythmicity across multiple biological scales, from central clock-mediated synchronization to peripheral clocks within epithelial cells, stromal cells, adipocytes, and immune populations. Emphasis is placed on the spatiotemporal regulation of antitumor immunity within the TME. At the same time, dendritic cell migration, antigen presentation, CD8 + T cell infiltration, and T cell exhaustion display time-dependent features that influence the efficacy of immune surveillance and immunotherapy. These findings supported a four-dimensional view of the TME, in which biological timing is a critical determinant of immune competence. We further discussed emerging therapeutic strategies that exploit circadian biology, including small-molecule clock modulators, rhythm-responsive nanomedicine, chronologically optimized CAR-T cell therapy, and time-of-day-dependent immune checkpoint blockade. Although most mechanistic evidence remains preclinical, and many clinical observations are retrospective, current data suggest that treatment timing may be a modifiable, low-cost parameter for improving anti-tumor efficacy while reducing toxicity. Finally, we highlighted future opportunities in microbiome-informed chronotherapy, multi-omics profiling, and digital twin modeling. Integrating temporal information into oncology may shift precision medicine from a static biomarker-driven framework toward a dynamic, time-resolved therapeutic paradigm.