Epidemiological studies link light at night (LAN), shift work, chronic jet lag (CJL), and core clock gene mutations to higher cancer risk and aggressive spread, especially in breast and colorectal cancer. The International Agency for Research on Cancer (IARC) classifies circadian disruption as a Group 2A carcinogen. At the molecular level, the clock runs a transcription-translation feedback loop (TTFL) involving brain and muscle ARNT-like protein 1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), period (PER), cryptochrome (CRY), REV-ERB, and retinoic acid-related orphan receptor (ROR) proteins, yet how these rhythms reshape the tumor microenvironment (TME) at each metastatic step remains unclear. Given these challenges, there is a need for in-depth research on the spatiotemporal mechanisms by which circadian disruption remodels the TME and drives metastasis.
The review was led by researchers at the Shanghai Geriatric Medical Center, Zhongshan Hospital, Fudan University and Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, with collaborators. Published (DOI: 10.20892/j.issn.2095-3941.2025.0491) in Cancer Biology & Medicine, the review synthesizes recent single-cell RNA sequencing, intravital imaging, and mechanistic studies to map how circadian clocks regulate immune suppression, angiogenesis, extracellular matrix remodeling, intravasation, circulation, extravasation, exosome signaling, and cell-cycle control within the metastatic tumor microenvironment.
The review describes stage-specific circadian control. At the invasive edge, clock genes influence epithelial-to-mesenchymal transition (EMT), matrix metalloproteinases (MMPs), and cancer stem cells (CSCs); BMAL1 can suppress migration in some tumors but promote metastasis in others by upregulating MMP9, while PER2 restrains EMT-linked transcription. During intravasation, circadian disruption shifts macrophage states and cytokine networks, including transforming growth factor-beta (TGF-β) and interleukin-6 (IL-6), helping tumor cells enter blood vessels. In circulation, circulating tumor cell (CTC) numbers and platelet activity fluctuate over 24 hours, and endothelial adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) show rhythmic expression that gates extravasation. The review also highlights clock-controlled angiogenesis via vascular endothelial growth factor (VEGF), immune evasion through myeloid-derived suppressor cells (MDSCs) and natural killer (NK) cells, exosome secretion via RAB27A, and cell-cycle checkpoints involving WEE1, cyclin B1, and p21. Clock-driven immune suppression also involves regulatory T cells and cancer-associated fibroblasts (CAFs), while REV-ERB agonists and CRY1-targeting compounds have shown early preclinical promise. A central message is context dependence: the same clock component can promote or suppress metastasis depending on tumor type, stage, and timing. The authors propose that mapping these rhythms could reveal when metastatic niches are most vulnerable.
The authors said the field is moving beyond simply listing clock-cancer associations to asking when and where metastatic niches become permissive. They said that because core clock components can either restrain or accelerate spread depending on tumor type, stage, and time of day, future studies must combine time-series single-cell RNA sequencing, circadian proteomics, and intravital imaging. They said such work could identify narrow treatment windows and help explain why some patients respond differently to immunotherapy or chemotherapy depending on when treatment is given. They added that standardized timing in trials will be essential for translating these insights.
If confirmed in patients, these findings could support chronotherapy—timing chemotherapy, radiotherapy, or immunotherapy to periods when tumors and their microenvironment are most vulnerable. Clock-modulating drugs, including BMAL1-targeting compounds and REV-ERB agonists, are early-stage possibilities, but their safety and specificity require rigorous testing. The review also calls for standardized reporting of Zeitgeber time (ZT), light-dark cycles, sex, age, and time-aware statistics in circadian cancer research. Clinically, trials may need to record sample collection time, treatment delivery phase, and patient chronotype. Such steps could turn circadian biology from a descriptive risk factor into a practical tool for precision oncology and metastasis prevention. For patients, this could mean smarter schedules rather than new drugs alone.
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References
DOI
10.20892/j.issn.2095-3941.2025.0491
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0491
Funding information
This research was supported by the National Natural Science Foundation of China (Grant No. 82405067), the Shanghai Municipal Health Commission (Grant No. 2019SY017), the Shanghai Municipal Health Commission Scientific Research Project (Grant No. 20254Y0181), and the Youth Development Program, Scientific Research Project of Shanghai Geriatric Medical Center (Grant No. YQ2025-007).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).