Review ArticleReview
Open Access

Circadian-driven transcriptional programs govern metastatic progression

Jie Wang, Hao Pan, Xuan Wang, Yuru Ren, Yiwen Huang, Yizhou Liu, Hejin Lai, Zhimin Fei, Ning Pu and Yu Wang
Cancer Biology & Medicine September 2026, 23 (9) 1213-1229; DOI: https://doi.org/10.20892/j.issn.2095-3941.2025.0491

Abstract

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.

keywords

Introduction

The central circadian clock resides in the suprachiasmatic nuclei (SCN) in mammals, where the central circadian clock regulates and synchronizes peripheral clocks across various tissues and organs1. The circadian clock operates through a fundamental transcription–translation negative feedback loop (TTFL) on the molecular scale. Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL, also referred to as BMAL1) and circadian locomotor output cycles kaput (CLOCK) form a positive feedback loop by interacting with E-box enhancer elements during the daytime, thereby inducing the transcription of inhibitory genes, such as period (PER1, PER2, and PER3) and cryptochrome (CRY1 and CRY2). PER and CRY proteins assemble into complexes that translocate into the nucleus at night, where PER and CRY inhibit the transcriptional activity of the CLOCK/ARNTL heterodimer. In addition, PER and CRY proteins are degraded via β-TrCP and FBXL3, which are E3 ligase complexes. This process leads to a gradual reduction in PER and CRY protein levels. As a result, the negative feedback inhibition is lifted, allowing CLOCK and BMAL1 to regain transcriptional activity. This restoration initiates a new transcriptional cycle, which begins afresh the following morning. The second regulatory loop of the circadian system involves CLOCK/ARNTL (BMAL1)-driven transcription of REV-ERBα/β (NR1D1/2) and retinoic acid-related orphan receptors (RORs), which are key nuclear receptors modulating rhythmic gene expression. BMAL1 expression is inhibited by REV-ERBα/β and activated by RORs, ensuring dynamic circadian rhythm control2. The third feedback loop includes the proline-rich and acidic amino acid-rich basic leucine zipper (PAR-bZIP), which involves activators, like albumin D-element-binding protein (DBP), thyrotrophic embryonic factor (TEF), and hepatic leukemia factor (HLF). It also features the transcription repressor known as nuclear factor interleukin 3-regulated (NFIL3, also referred to as E4BP4). These factors compete for binding to the D-box element, thereby modulating the transcription of downstream target genes (Figure 1)3.

The TTFL of circadian rhythm. The circadian clock is organized around the TTFL composed of three interlocked regulatory loops that coordinate rhythmic gene expression across the day–night cycle. 1. Core feedback loop: During the daytime, the heterodimeric transcription factors, CLOCK and BMAL1, bind to E-box elements in the nucleus, activating the transcription of core CLOCK genes, including PERs and CRYs, as well as CLOCK-controlled genes, such as DBP, RORs, and REV-ERBs. Newly synthesized PER and CRY proteins accumulate in the cytoplasm during the night, where CK1 phosphorylates PER proteins, regulating the stability and timing of nuclear entry. Phosphorylated PER/CRY complexes translocate into the nucleus and inhibit CLOCK/BMAL1-mediated transcription. Subsequently, PER and CRY proteins are ubiquitinated and degraded by the proteasome, thereby relieving negative feedback and allowing a new circadian cycle to begin. 2. Secondary feedback loop: In the secondary feedback loop, CLOCK/BMAL1-driven transcription induces the nuclear receptors, REV-ERBs and RORs, which competitively bind to same ROREs in the promoters of circadian genes. Through RORE-dependent mechanisms, REV-ERBs repress whereas RORs activate BMAL1 transcription, thereby stabilizing oscillatory amplitude and phase. Beyond regulating core clock components, RORE-mediated signaling contributes to the phase-aligned expression of downstream clock-associated regulators, including NFIL3, providing a temporal connection between the secondary feedback loop and D-box-dependent circadian output. 3. Third feedback loop: The loop involves DBP and NFIL3, which competitively bind to D-box elements to regulate rhythmic transcription of downstream clock-controlled genes, thereby contributing to circadian output that is temporally coordinated with ROR-mediated regulation. BMAL1, brain and muscle ARNT-like protein1; CK1, casein kinase 1; CLOCK, circadian locomotor output cycles kaput; CRYs, cryptochromes, CRY1, CRY2; DBP, d-element-binding protein; NFIL3, nuclear factor interleukin 3; PERs, period circadian regulators, PER1, PER2, PER3; RORs, retinoic acid receptor-related orphan receptors, RORα, RORβ, RORγ; RORE, ROR response element; REV-ERBs, nuclear receptor subfamily 1 group d members, REV-ERBα, REV-ERBβ; TTFL, transcription–translation feedback loop.
Figure 1

The TTFL of circadian rhythm. The circadian clock is organized around the TTFL composed of three interlocked regulatory loops that coordinate rhythmic gene expression across the day–night cycle. 1. Core feedback loop: During the daytime, the heterodimeric transcription factors, CLOCK and BMAL1, bind to E-box elements in the nucleus, activating the transcription of core CLOCK genes, including PERs and CRYs, as well as CLOCK-controlled genes, such as DBP, RORs, and REV-ERBs. Newly synthesized PER and CRY proteins accumulate in the cytoplasm during the night, where CK1 phosphorylates PER proteins, regulating the stability and timing of nuclear entry. Phosphorylated PER/CRY complexes translocate into the nucleus and inhibit CLOCK/BMAL1-mediated transcription. Subsequently, PER and CRY proteins are ubiquitinated and degraded by the proteasome, thereby relieving negative feedback and allowing a new circadian cycle to begin. 2. Secondary feedback loop: In the secondary feedback loop, CLOCK/BMAL1-driven transcription induces the nuclear receptors, REV-ERBs and RORs, which competitively bind to same ROREs in the promoters of circadian genes. Through RORE-dependent mechanisms, REV-ERBs repress whereas RORs activate BMAL1 transcription, thereby stabilizing oscillatory amplitude and phase. Beyond regulating core clock components, RORE-mediated signaling contributes to the phase-aligned expression of downstream clock-associated regulators, including NFIL3, providing a temporal connection between the secondary feedback loop and D-box-dependent circadian output. 3. Third feedback loop: The loop involves DBP and NFIL3, which competitively bind to D-box elements to regulate rhythmic transcription of downstream clock-controlled genes, thereby contributing to circadian output that is temporally coordinated with ROR-mediated regulation. BMAL1, brain and muscle ARNT-like protein1; CK1, casein kinase 1; CLOCK, circadian locomotor output cycles kaput; CRYs, cryptochromes, CRY1, CRY2; DBP, d-element-binding protein; NFIL3, nuclear factor interleukin 3; PERs, period circadian regulators, PER1, PER2, PER3; RORs, retinoic acid receptor-related orphan receptors, RORα, RORβ, RORγ; RORE, ROR response element; REV-ERBs, nuclear receptor subfamily 1 group d members, REV-ERBα, REV-ERBβ; TTFL, transcription–translation feedback loop.

Early clinical evidence suggests that factors disrupting circadian rhythms, including light at night (LAN) and night-shift work, correlate with a higher cancer risk4. These disturbances have been connected to the promotion of tumor metastasis in breast5 and colorectal cancer (CRC)6. Rather than solely a direct result of the tumor, tumor development and dissemination are profoundly influenced by the complex tumor microenvironment (TME) in which the tumor originates, invades, and spreads7. The TME can support and hinder tumor progression, which contributes to extracellular matrix (ECM) remodeling and tumor support involving endothelial cells (ECs) and mesenchymal cells8. The TME is vital in each stage of metastatic progression, including edge invasion, intravasation, circulation, extravasation, and colonization in the secondary organs9. The TME also significantly affects metastasis processes by influencing immune evasion and suppression, promoting angiogenesis, and epithelial-to-mesenchymal transition (EMT), all of which contribute to tumor progression and spread9. Circadian disruption results in remodeling of tumor-associated immune cells in tumor tissues, which involves changes in the temporal dynamics and switching of M1 and M2 macrophage populations, thus accelerating tumor progression10. Our previous studies have primarily emphasized the roles of various circadian disruption models in tumorigenesis11, as well as the differential effects on the tumor and the microenvironment during metastasis12. This review comprehensively focuses on how the circadian clock influences tumor metastasis through different stages of metastasis, which is integral to the invasion-metastasis cascade and drives cancer progression through the multistep process.

Clinical relevance between circadian disruption and tumor metastasis

Circadian rhythms have been shown in previous studies and reports to be associated with various types of cancers. Circadian disruption was categorized as a Group 2A carcinogen by the International Agency for Research on Cancer (IARC) as early as 200713. The interference effect of nocturnal shift schedules, nighttime illumination, and social time misalignment, which exhibit irregular patterns of melatonin secretion, are positively linked to the tendency toward breast cancer, prostate cancer, and CRC14,15. Despite growing interest, clinical data on how circadian disruption influences tumor metastasis are still scarce. Melatonin and cortisol metabolism fluctuates by means of the interrelationship between the sleep-wake cycle and the internal biological clock. Of note, circadian disruption may reverse melatonin and cortisol rhythms16. An abnormal early-night peak in cortisol levels occurs in patients with advanced breast cancer (ABC) that is strongly associated with disease-free survival (DFS)17. In addition, circadian disruption promotes fatigue18 and depression19, which are significantly associated with increased metastasis and shorter survival. The differential regulation of clock genes in primary and metastatic tumors of cancer patients has been thoroughly studied.

A meta-analysis was conducted involving 36 studies involving 7,476 cancer patients to assess the prognostic impact of clock gene expression regulators of cellular functions, like cell cycle control, DNA repair, and apoptosis20. Downregulation of PER1 and PER2 is strongly correlated with poor tumor differentiation, advanced TNM stages, increased metastasis, and shorter overall survival (OS), highlighting the potential role as key prognostic markers and regulators in cancer progression. To explore the association of circadian disruption in endocrine-associated tumors, Kuo and his team21 found that the promoters of BMAL1, PER1, PER2, and CRY1 exhibit hypermethylation in breast cancer samples. Moreover, BMAL1 and PER2 were relevant to metastasis of lymph nodes21.

Furthermore, upregulation of circadian regulatory genes, such as CLOCK, PER1-3, CRY2, NPAS2, and RORC, has an active role in survival without metastasis, suggesting a prognostic value in breast cancer. Notably, circadian clock functionality was preserved in slow growth, localized behavior, and non-metastatic tumors but disappeared in aggressive phenotypes, like ER+ and HER2+ breast cancer22. Whole-exome sequencing was used to compare mutations of genes between primary tumor tissues and liver metastases in CRC and analysis via KEGG pathways revealed a significant enrichment of mutations in genes associated with the circadian clock23. Further studies compared clock gene expression in primary CRC, colorectal liver metastases (CRLMs), and liver tissue. The level of PER124 and PER3 expression was negatively related to the number of CRLMs, whereas, BMAL124, BMAL225, and CLOCK facilitated CRC metastasis. An opposing relationship was identified between expression of BMAL1 and distant tumor metastasis in patients with nasopharyngeal carcinoma26. TIMELESS is a conserved protein that maintains circadian oscillations of mammals and controls cellular metabolism27. Overexpression of TIMELESS has been strongly associated with poor clinical outcomes in human cervical cancer. Specifically, elevated levels of TIMELESS correlates with increased lymphovascular space involvement, which has a vital role in cervical cancer metastasis and progression. REV-ERBα, part of the nuclear hormone receptor group, inhibits tumor and lymph node metastasis in human gastric cancer28. Moreover, a reduction in HLF expression has a correlation with early progression and metastatic spread in patients with NSCLC29.

In summary, the connection between clock genes and tumor metastasis appears to be tissue-specific and context-dependent, and differs across various types of tissues. However, transcriptional clock genes act as factors inhibiting tumor metastasis, whereas the CLOCK/BMAL1 complex acts as a promoter of metastasis in the majority of human cancers, suggesting a vital role in transcriptional activities (Table 1). Dysregulation of circadian oscillations can cause tumor metastasis and influence clinical outcomes. The circadian clock and metastasis present opportunities to enhance therapeutic strategies. Combining compounds that modulate clock gene activity with first-line therapies, such as chemotherapy, radiotherapy, or immunotherapy, could improve therapeutic efficacy. This approach not only enhances tumor control but also reduces resistance to conventional treatments, offering a novel and personalized strategy for managing cancer.

View this table:
Table 1

CLOCK gene expression across various cancer types

Circadian clock mechanisms underlying tumor metastasis

The spread of cancer occurs as tumor cells develop mechanisms to avoid immune detection and invade the circulatory system. Tumor metastasis involves the following five stages: edge invasion; intravasation; circulation; extravasation; and colonization in the distant organ9. In this section, we will first elaborate on the roles of circadian rhythms in immune suppression and angiogenesis, which will be followed by a discussion of how circadian rhythms influence the TME at each stage of metastasis.

Circadian rhythm and immune suppression

A pivotal aspect of malignant tumor progression is the ability to evade and suppress the host immune system. This process is always accomplished by suppressing various effector immune cells, or more commonly, by stimulating immunosuppressive cells, including myeloid-derived suppressor cells (MDSCs). MDSCs inhibit immunosurveillance by inhibiting antigen presentation, suppressing T cell activation, altering macrophage polarization, and reducing NK cell cytotoxicity30. The circadian clock inherently modulates the action and functionality of immune cells31. LAN, a method used to induce circadian disruption, promotes the recruitment of CD11b+Ly6GhighCD11b+CD49d+MDSCs, thereby fostering an immunologic inhibitory surrounding32. Chronic jet lag (CJL) also promotes the recruitment of MDSCs by establishing an immunosuppressive environment through the CXCL5-CXCR2 signaling pathway in bone marrow metastases and breast cancer lung metastases33. In addition, CJL impairs NK cell cytotoxicity and suppresses CD122 transcription, thereby further promoting tumor progression34,35.

In addition to light disruption, inhibition of clock gene oscillation contributes to the abnormal immune landscape in gliomas, which features high PD-L1 and CTLA-4 expression36. The positive feedback loop gene, BMAL1, correlates positively with CD4+ T cell and neutrophil penetration, and dendritic cells (DCs), indicating anti-tumor activity37. The negative feedback loop genes (PER2 but not PER1), which are transcribed by the BMAL1/CLOCK complex, are pivotal in forming a microenvironment that suppresses tumor progression that is characterized by the accumulation of collagen and the presence of cancer-associated fibroblasts (CAFs)38. Similarly, the nuclear receptors and retinoic acid-related orphan receptors (RORα and RORγ) have an important role in immune suppression. RORα has a major role in preserving cholesterol balance in CD8+ T cells through suppression of the NF-κB-mediated transcriptional regulation by altering the status of T cells from dormant-to-cytotoxic39. Moreover, RORα inhibits activation of proliferative target genes in fibroblasts through the Wnt/β-catenin pathway40. RORγ is a key transcription factor that promotes innate immune activation, including the differentiation and function of CD4+Th17 and CD8+Tc17 cells41, and simultaneously alleviating immune suppression by inhibiting T regulatory cell (Treg) development and reducing the expression of co-inhibitory receptors on tumor-reactive lymphocytes42. Immune suppression has a crucial role in tumor initiation and growth. The above studies indicated that most clock genes inhibit tumor metastasis by reshaping immune cell activity. These findings suggested a link between circadian rhythms and immune suppression, highlighting the significant impact on tumor progression (Figure 2).

Circadian clock-specific TME that affects immune suppression and angiogenesis. Schematic illustration of how circadian clock components modulate immune suppression and angiogenesis in the TME. (A) Circadian regulation of immune suppression. Core clock genes, including BMAL1, BMAL2, CLOCK, PER2, RORα, and RORγ, influence the differentiation, function, and metabolic state of multiple immune cell populations within the TME. Circadian regulation affects CAFs, CD8+ T cells, CD4+ T cells, Tregs, DCs, and neutrophils, thereby shaping immunosuppressive signaling pathways, such as NF-κB and metabolic processes, including cholesterol metabolism. In parallel, circadian disruption, exemplified by CJL, promotes the accumulation and suppressive activity of MDSCs through the CXCL5–CXCR2 axis and impairs NK cell function via altered CD122 signaling, collectively enhancing immune suppression. (B) Circadian regulation of angiogenesis. Circadian clock components, including CLOCK, BMAL1, PER2, and RORα, regulate angiogenic processes by modulating VEGF signaling in ECs. Disruption of circadian rhythms, such as exposure to LL, enhances VEGF-driven angiogenesis, thereby facilitating tumor vascularization. BMAL1, brain and muscle ARNT-like protein1; BMAL2, brain and muscle ARNT-like protein2; CAFs, cancer-associated fibroblasts; CJL, chronic jet lag; CXCL5, C-X-C motif chemokine ligand 5; CXCR2, C-X-C motif chemokine receptor 2; DCs, dendritic cells; ECs, endothelial cells; LL, constant light; MDSCs, myeloid-derived suppressor cells; NK cells, natural killer cells; PER2, period circadian regulator 2; RORα/γ, retinoic acid receptor-related orphan receptor alpha/gamma; TME, tumor microenvironment; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.
Figure 2

Circadian clock-specific TME that affects immune suppression and angiogenesis. Schematic illustration of how circadian clock components modulate immune suppression and angiogenesis in the TME. (A) Circadian regulation of immune suppression. Core clock genes, including BMAL1, BMAL2, CLOCK, PER2, RORα, and RORγ, influence the differentiation, function, and metabolic state of multiple immune cell populations within the TME. Circadian regulation affects CAFs, CD8+ T cells, CD4+ T cells, Tregs, DCs, and neutrophils, thereby shaping immunosuppressive signaling pathways, such as NF-κB and metabolic processes, including cholesterol metabolism. In parallel, circadian disruption, exemplified by CJL, promotes the accumulation and suppressive activity of MDSCs through the CXCL5–CXCR2 axis and impairs NK cell function via altered CD122 signaling, collectively enhancing immune suppression. (B) Circadian regulation of angiogenesis. Circadian clock components, including CLOCK, BMAL1, PER2, and RORα, regulate angiogenic processes by modulating VEGF signaling in ECs. Disruption of circadian rhythms, such as exposure to LL, enhances VEGF-driven angiogenesis, thereby facilitating tumor vascularization. BMAL1, brain and muscle ARNT-like protein1; BMAL2, brain and muscle ARNT-like protein2; CAFs, cancer-associated fibroblasts; CJL, chronic jet lag; CXCL5, C-X-C motif chemokine ligand 5; CXCR2, C-X-C motif chemokine receptor 2; DCs, dendritic cells; ECs, endothelial cells; LL, constant light; MDSCs, myeloid-derived suppressor cells; NK cells, natural killer cells; PER2, period circadian regulator 2; RORα/γ, retinoic acid receptor-related orphan receptor alpha/gamma; TME, tumor microenvironment; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.

Circadian rhythm and angiogenesis

Angiogenesis has a key role in invasive tumor expansion, metastasis, and deregulation of dormancy in second organs43. Some evidence has indicated that regulation of cellular circadian clock machinery can occur directly and indirectly through angiogenic processes. Peripheral circadian regulators within the vasculature are broadly presented in the ECs, vascular smooth muscle cells (VSMCs), and pericytes44. Recent studies by Teleanu and colleagues43 have revealed the functional impact of elevated BMAL1 expression in VSMCs. Takaguri et al.45 reported that BMAL1 partially mediates the proliferative response of VSMCs to platelet-derived growth factor-BB (PDGF-BB) through the ERK signaling pathway. The circadian disruption influences pro-angiogenic factors as well, which oscillate in a circadian pattern, including vascular endothelial growth factor (VEGF), bFGF, IGFBP and EGF46. Yasuniwa47 used tumor-bearing mice under constant light (LL) and showed a decreased level of VEGF, revealing that circadian disruption led to inhibited angiogenesis and elevated levels of various pro-angiogenic factors. The amount of VEGF in tumor tissue exhibited a stronger expression peak at nighttime compared to the daytime in a carcinogen-induced mouse sarcoma model48. Circadian genes serve as pro-49 and anti-angiogenic factors50. PER2 regulation is context-dependent and varies across different tumor types and models. RORα exhibits an anti-angiogenic phenotype, whereas BMAL1 acts as a pro-angiogenic factor under tissue ischemia and can directly bind to the VEGF gene promoter, thereby modulating the VEGF gene promoter activity51,52. Overall, circadian genes are deeply involved in tumor angiogenesis and the regulatory effects vary depending on the tumor type and model (Figure 2).

Circadian and invasive edge

The invasive edge refers to the interface between the tumor bulk and the surrounding normal parenchyma, where malignant cells penetrate the basement membrane and begin to infiltrate nearby tissues. Tumor cells display substantial molecular diversity and phenotypic adaptability within this area, involving reorganization of the cytoskeleton, enhanced expression of matrix-degrading enzymes, such as matrix metalloproteinases (MMPs), modified adhesion properties, and induction of EMT. These invasive front cells exhibit high motility and aggressiveness and are widely recognized as the precursors driving tumor dissemination and relapse.

The EMT represents one of the earliest stages of primary tumor invasion, a phenotypic shift that facilitates tumor cell migration and subsequent entry into the circulatory system53. Core circadian transcription factors have a dual role in EMT formation, both promoting and inhibiting EMT formation. BMAL1 can reduce the migratory and invasive capabilities of U87MG54, lung cancer, and glioma cells55 via blocking the PI3K-Akt-MMP-2, MMP9 pathways, a classical pathway of EMT. Furthermore, BMAL1 inhibits intracellular ROS-induced EMT via TGF-ß signaling56. The expression of TGF-β pathway-related genes, including TGF-β1, SMAD3, SMAD4, and SMAD7, fluctuates according to circadian rhythms. Among these genes, SMAD4 enhances invasiveness and chemosensitivity of pancreatic ductal adenocarcinoma (PDA) cells57. Conversely, overexpression of BMAL1 enhances the metastatic potential of some tumors. For example, BMAL1 overexpression promotes breast cancer cell metastasis by upregulating MMP9 expression58. CLOCK has been shown to enhance EMT in CRC and is markedly correlated with late-stage TNM classification and lymphatic metastasis6. Moreover, CLOCK and BMAL1 regulate the RHOA–ROCK–CFL signaling axis, thereby modulating F-actin/G-actin turnover and facilitating the proliferation, migration, and invasion of cancer cells59. However, PER2 serves as a transcript co-repressor to suppress the expression of EMT in breast epithelial and tumor cell lines via recruited polycomb proteins (EZH2, SUZ12, and HDAC2) to octamer transcription factor 1 (OCT1) binding sites of the TWIST1 and SLUG promoters60. Above all, these findings indicate that circadian regulation at the invasive edge is context-dependent, varying across tumor types and models.

Moreover, cancer stem cells (CSCs), defined by self-renewal, differentiation, and invasive capabilities, are promoted by EMT and hypoxic conditions61–63. There are also strong associations between circadian and CSCs. Chronic circadian disruption (CRD) leads to an increase in the population of breast CSCs. In these cells, particularly in aldehyde dehydrogenase (ALDH)-positive cells, clock genes fail to exhibit rhythmic expression. This observation implies that clock gene activity may be suppressed within CSCs33. With respect to clock genes, the CLOCK/BMAL1 heterodimer participates in maintaining glioma stem cells (GSCs) and immunosuppression via the enhanced transcription of olfactomedin-like3 (OLFML3), a newly identified chemokine that attracts microglia and suppresses immune responses64. A CLOCK-OLFML3-HIF1α-legumain (LGMN)-CD162 signaling axis has been identified in glioblastoma multiforme (GBM), highlighting the role in driving intratumoral immune suppression in the TME65. Application of REV-ERB agonists (SR9009 and SR9011) specifically promote CSC differentiation66, impair the GSC maintaining an undifferentiated state together with self-renewal ability, and cause cell-cycle arrest with apoptosis in GBM67. PER2 and PER3 negatively regulate breast cancer stemness68 and prostate cancer stem cells, respectively69. Taken together, positive feedback of the CLOCK/BMAL1 heterodimer may be crucial for CSC maintenance, while negative feedback of genes may inhibit cancer stemness (Figure 3).

Circadian clock-specific TME that affect invasive edge. Schematic illustration of the context-dependent roles of circadian clock components in regulating tumor invasion at the invasive edge. (1) EMT initiation: At the early stage of tumor invasion, core circadian regulators, including BMAL1, CLOCK, and PER2, participate in EMT initiation. This process is associated with increased MMP2/9 expression, altered F-actin dynamics, and regulation of EMT-related transcription factors (TWIST1 and SLUG), together with TGF-β-related signaling, thereby facilitating the transition from epithelial-to-mesenchymal phenotypes. (2) Invasive edge formation: At the invasive edge, circadian regulation is associated with the CSC-like states and collective invasive behavior. The CLOCK/BMAL1 axis has been implicated in promoting invasive phenotypes through downstream signaling modules (e.g., OLFML3–LGMN–CD162), whereas negative-feedback clock components, such as REV-ERBs and PER2 are associated with the modulation of stemness-related properties. External circadian perturbation, such as CJL, may further influence tumor cell behavior at the invasive edge. BMAL1, brain and muscle ARNT-like protein 1; CLOCK, circadian locomotor output cycles kaput; CJL, chronic jet lag; EMT, epithelial–mesenchymal transition; MMP2/9, matrix metalloproteinase 2/9; PER2, period circadian regulators 2; REV-ERBs, nuclear receptor subfamily 1 group D; SLUG, snail family transcriptional repressor 2; TGFβ, transforming growth factor beta; TWIST1, twist family bHLH transcription factor 1.
Figure 3

Circadian clock-specific TME that affect invasive edge. Schematic illustration of the context-dependent roles of circadian clock components in regulating tumor invasion at the invasive edge. (1) EMT initiation: At the early stage of tumor invasion, core circadian regulators, including BMAL1, CLOCK, and PER2, participate in EMT initiation. This process is associated with increased MMP2/9 expression, altered F-actin dynamics, and regulation of EMT-related transcription factors (TWIST1 and SLUG), together with TGF-β-related signaling, thereby facilitating the transition from epithelial-to-mesenchymal phenotypes. (2) Invasive edge formation: At the invasive edge, circadian regulation is associated with the CSC-like states and collective invasive behavior. The CLOCK/BMAL1 axis has been implicated in promoting invasive phenotypes through downstream signaling modules (e.g., OLFML3–LGMN–CD162), whereas negative-feedback clock components, such as REV-ERBs and PER2 are associated with the modulation of stemness-related properties. External circadian perturbation, such as CJL, may further influence tumor cell behavior at the invasive edge. BMAL1, brain and muscle ARNT-like protein 1; CLOCK, circadian locomotor output cycles kaput; CJL, chronic jet lag; EMT, epithelial–mesenchymal transition; MMP2/9, matrix metalloproteinase 2/9; PER2, period circadian regulators 2; REV-ERBs, nuclear receptor subfamily 1 group D; SLUG, snail family transcriptional repressor 2; TGFβ, transforming growth factor beta; TWIST1, twist family bHLH transcription factor 1.

Circadian rhythm and intravasation

In addition to developing an invasive phenotype in primary tumors, the critical phase in the metastatic cascade is the process of blood vessels into the bloodstream, which is known as intravasation70. Tumor associated macrophages (TAMs) are within the TME. Increasing evidence suggests that TAMs promote tumor progression by means of various mechanisms, primarily by facilitating intravasation71. Therefore, we will elucidate the functions of the circadian clock on TAMs in this chapter.

First, TAMs are positioned to blood vessels, assisting cancer cells in entering the bloodstream through intravasation72. Some studies have suggested that circadian regulates macrophage secretion and polarization. The study of Sun et al.73 revealed that macrophages are increased in CRD tissues and further aggravate the risk of cancer. CRD enhanced tumor progression by altering or reversing the day-night cycles of M1 and M2 macrophages in a model of melanoma, along with concentrations of cytokines in spleen and tumor tissues74. Moreover, the cell movement and phagocytosis of macrophages are inversely correlated with levels of BMAL1, suggesting that clock genes regulate some aspects of immunity75. Furthermore, BMAL1 directly modulates the transcriptional function of NRF2, antioxidative function involved in the regulation of IL-1β in macrophages and drives pro-inflammatory and oncogenic signals76. It has also been reported that BMAL1 retains mitochondrial oxidative metabolism, while reducing oxidative stress to regulate HIF-1α activity, and specific BMAL1 knockout in TAMs facilitates an immunosuppressive TME77. With respect to negative clock loops, REV-ERBα, an orphan nuclear receptor, suppresses macrophage inflammatory responses by directly regulating CCL2 expression78. RORα has a vital role in regulating macrophages by decreasing the pro-inflammatory cytokines release in vivo79. It is unclear how the circadian rhythm modulates macrophages during tumor intravasation. Further research is needed to address whether the circadian rhythm hijacks tumor cell intravasation into circulation by regulating resident or myeloid macrophage recruits (Figure 4).

Circadian clock-specific TME that affect intravasation, circulation, and extravasation. Schematic illustration of how circadian clock components regulate key steps of tumor cell dissemination, including intravasation, circulation, and extravasation, through interactions with the TME, exosome-mediated communication, and CRD. (A) Intravasation. ① The CLOCK/BMAL1 heterodimer activates the expression of NRF2, thus inhibiting secretion of IL-1β in macrophage. The CLOCK/BMAL1 heterodimer binds to the E-box to maintain the mitochondrial metabolism of macrophage homeostasis. ② RORα induces the expression of CCL2, while REV-ERBα inhibits CCL2 in macrophages. ③ CRD promotes the transition of M1 macrophages to M2 macrophages. (B) Circulation. During circulation, disseminated tumor cells are exposed to a dynamic vascular environment under conditions of circadian disruption. Circadian clock components, including BMAL1, PER2, and REV-ERBα, are associated with the regulation of tumor cell interactions with endothelial cells, platelets, and immune cells within the bloodstream, which together influence tumor cell survival and behavior during circulation. (C) Extravasation. Circadian clock genes, including CLOCK, BMAL1, and PER2, regulate endothelial activation and barrier function during extravasation. Rhythmic modulation of adhesion molecules, such as ICAM-1, together with NO signaling, influences tumor cell arrest and transmigration across the endothelium. SD and CRD exacerbate endothelial dysfunction, facilitating tumor cell extravasation into distant tissues. BMAL1, brain and muscle ARNT-like protein 1; CAF, cancer-associated fibroblast; CLOCK, circadian locomotor output cycles kaput; CRD, circadian rhythm disruption; CSCs, cancer stem cells; CCL2, C-C motif chemokine ligand 2; ECs, endothelial cells; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin-1 beta; NO, nitric oxide; NRF2, nuclear factor erythroid 2-related factor 2; PER1/2, period circadian regulators 1/2; RAB27A, RAB27A member RAS oncogene family; REV-ERBα, nuclear receptor subfamily 1 group D member 1; RORs, retinoic acid receptor-related orphan receptors; SD, sleep disruption; TME, tumor microenvironment.
Figure 4

Circadian clock-specific TME that affect intravasation, circulation, and extravasation. Schematic illustration of how circadian clock components regulate key steps of tumor cell dissemination, including intravasation, circulation, and extravasation, through interactions with the TME, exosome-mediated communication, and CRD. (A) Intravasation. ① The CLOCK/BMAL1 heterodimer activates the expression of NRF2, thus inhibiting secretion of IL-1β in macrophage. The CLOCK/BMAL1 heterodimer binds to the E-box to maintain the mitochondrial metabolism of macrophage homeostasis. ② RORα induces the expression of CCL2, while REV-ERBα inhibits CCL2 in macrophages. ③ CRD promotes the transition of M1 macrophages to M2 macrophages. (B) Circulation. During circulation, disseminated tumor cells are exposed to a dynamic vascular environment under conditions of circadian disruption. Circadian clock components, including BMAL1, PER2, and REV-ERBα, are associated with the regulation of tumor cell interactions with endothelial cells, platelets, and immune cells within the bloodstream, which together influence tumor cell survival and behavior during circulation. (C) Extravasation. Circadian clock genes, including CLOCK, BMAL1, and PER2, regulate endothelial activation and barrier function during extravasation. Rhythmic modulation of adhesion molecules, such as ICAM-1, together with NO signaling, influences tumor cell arrest and transmigration across the endothelium. SD and CRD exacerbate endothelial dysfunction, facilitating tumor cell extravasation into distant tissues. BMAL1, brain and muscle ARNT-like protein 1; CAF, cancer-associated fibroblast; CLOCK, circadian locomotor output cycles kaput; CRD, circadian rhythm disruption; CSCs, cancer stem cells; CCL2, C-C motif chemokine ligand 2; ECs, endothelial cells; ICAM-1, intercellular adhesion molecule 1; IL-1β, interleukin-1 beta; NO, nitric oxide; NRF2, nuclear factor erythroid 2-related factor 2; PER1/2, period circadian regulators 1/2; RAB27A, RAB27A member RAS oncogene family; REV-ERBα, nuclear receptor subfamily 1 group D member 1; RORs, retinoic acid receptor-related orphan receptors; SD, sleep disruption; TME, tumor microenvironment.

Circadian rhythm and circulation

Metastasis is an inherently inefficient process, as fewer than 0.01% of disseminated tumor cells successfully establish colonies at distant sites to form clinically detectable metastases, a process that is dependent on the circulatory system9. During dissemination, the platelets release TGF-β and platelet-derived growth factor (PDGF) to protect CTCs against shear stress and immune attacks80. CTC counts fluctuate with the circadian rhythm in multiple myeloma (MM) patients, peaking in the latter half of the night, indicating a potential preference for dissemination into peripheral circulation during rest81. A study using in vivo fluorescent flow cytometry revealed that CTC counts are higher during early stages in prostate cancer compared to advanced stages and exhibit a peak at the onset of the night within a 24-h cycle82.

Platelets also display a 24-h rhythm in aggregation and adhesion under the control of CLOCK genes. The enforced 20-h rest/activity cycle rhythms peaked with respect to platelet aggregation and adhesion with leukocytes and endothelial cells83. Under CRD conditions, platelets and immunoglobulin (IgM and IgE) counts are reduced84. Taken together, future investigations are warranted to fully elucidate the mechanisms underlying circadian clock-mediated regulation of CTC trafficking (Figure 4).

Circadian rhythm and extravasation

Extravasation of CTCs is a tightly regulated, multistep process requiring dynamic interactions between tumor cells and the vascular endothelium. Recent studies indicate that these interactions are temporally gated by the circadian clock, which coordinates endothelial adhesion, vascular tone, and barrier permeability. The compact structure of capillary endothelial walls contributes to organ-specific patterns of metastasis85. Circadian disruption, such as occurs in sleep deprivation (SD), impairs endothelial function via dysregulation of the nitric oxide (NO)-dependent vasodilatory pathway in mice and humans86. Core CLOCK genes, including BMAL1 and PER2, are positively associated with NO production and inversely related to endothelial nitric oxide synthase (eNOS) expression87, suggesting that rhythmic control of endothelial activation is integral to vascular homeostasis.

At the molecular level, adhesion molecules, such as ICAM-1 and VCAM-1, exhibit circadian oscillations under the regulation of CLOCK and BMAL1, thereby influencing the timing and efficiency of tumor cell attachment to the endothelium88,89. Likewise, circadian variation in eNOS activity and NO release modulates vascular relaxation and permeability, creating time-dependent windows that may favor or hinder tumor cell extravasation90,91. In specific vascular niches, such as the blood–brain barrier (BBB), clock-controlled expression of efflux transporters and tight junction proteins shapes rhythmic changes in barrier permeability, acting as a temporal gate for metastatic invasion92. Furthermore, pericytes, which reinforce microvascular stability, harbor intrinsic circadian clocks that synchronize with endothelial rhythms to maintain barrier integrity and regulate neurovascular coupling93.

Taken together, these findings support the view that cancer extravasation is temporally regulated by endothelial and perivascular clocks that control adhesion, NO signaling, and barrier function. While the mechanistic links connecting the circadian phase with platelet activation, cytokine release, and endothelial–tumor communication remain to be clarified88 (Figure 4).

Circadian rhythm and exosomes

Tumor-derived exosomes, small extracellular vesicles (EVs) secreted by the primary tumor, educate the environment to facilitate formation of the cancer premetastatic niche (PMN). It remains unclear whether EVs, which contain exosomes, facilitated intercellular communication among tissues and exhibit modulation in the circadian rhythm. Khalyfa and his research team94 observed that plasma exosomes undergo significant modifications when exposed to periodic alterations in environmental lighting. More recently, Yeung95 suggested that modulation of the rhythmic transcript and protein abundance by the circadian clock indirectly results in the time-specific loading of proteins into small EVs, revealing how exosomes facilitate temporal synchronization between and across different tissues. Moreover, BMAL1 has been shown to regulate Rab27a expression at the transcriptional level. Rab27a is a crucial molecule involved in exosome secretion, thereby promoting CRC metastasis96. In agreement with this finding, Fekry et al.97 emphasized that exosome secretion and cargo loading exhibit circadian rhythmicity, linking extracellular vesicle dynamics to temporal regulation of tumor development. Because this is a growing area of research, greater focus should be directed toward understanding how circadian rhythms promote the secretion of tumor-derived EVs.

Circadian rhythm and cell cycle regulation

Even if successfully seeded to distant organs, cancer cells must defy angiogenic, cellular, and immune dormancy to guarantee survival and expansion98. In the above sections, we have listed angiogenesis and immune suppression under circadian control. We will specifically introduce the cell cycle crosstalk with the circadian clock in this section (Figure 5).

Circadian clock cell-cycle crosstalk on tumor metastasis. Schematic illustration of the interactions between circadian clock components and cell-cycle regulators controlling transitions through G1, S, G2, and M phases. G1 phase: Cell-cycle entry is governed by cyclin D–Cdk4/6. Under CCD, cyclin D–Cdk4/6 activity is modulated with PER2 shown as an inhibitory regulator. p21/p27 act as checkpoint mediators at the G1/S boundary and are influenced by PER1, REV-ERBα, RORα, and CJL. These interactions collectively regulate progression toward the S phase. S phase: Progression through S phase involves cyclin E–Cdk2 and cyclin A–Cdk2 complexes. PER1 is linked to cyclin E–Cdk2 regulation, while REV-ERBα modulates cyclin A–Cdk2 activity, contributing to S-phase control. G2 phase: Transition into mitosis is coordinated by cyclin B–Cdk1. BMAL1/CLOCK regulate WEE1, which in turn modulates cyclin B–Cdk1 activity. CRY1 and PER1 influence WEE1, further integrating circadian control at the G2 checkpoint. M phase and G2/M checkpoint: Circadian components intersect with DDR pathways, including PER2–CHK2, CRY1–TIM–ATR–CHK1, and PER1–TIM–ATM–CHK2, which modulate cyclin B–Cdk1-dependent mitotic progression. External cues, such as DD are depicted as additional modulators at this stage. ATR, ATR serine/threonine kinase; ATM, ATM serine/threonine kinase; BMAL1, brain and muscle ARNT-like protein1; CCD, chronic circadian disruption; CDK, cyclin-dependent kinase; CHK1/2, checkpoint kinase1/2; Cdk1/2/4/6, cyclin dependent kinase 1/2/4/6; CLOCK, circadian locomotor output cycles kaput; CRY1, cryptochrome1; CJL, chronic jet-lag; DD, constant dark; PER1/2, period circadian regulator1/2; RORα, retinoic acid receptor-related orphan receptorα; REV-ERBα, nuclear receptor subfamily 1 group d member; TIM, timeless; WEE1, G2 checkpoint kinase.
Figure 5

Circadian clock cell-cycle crosstalk on tumor metastasis. Schematic illustration of the interactions between circadian clock components and cell-cycle regulators controlling transitions through G1, S, G2, and M phases. G1 phase: Cell-cycle entry is governed by cyclin D–Cdk4/6. Under CCD, cyclin D–Cdk4/6 activity is modulated with PER2 shown as an inhibitory regulator. p21/p27 act as checkpoint mediators at the G1/S boundary and are influenced by PER1, REV-ERBα, RORα, and CJL. These interactions collectively regulate progression toward the S phase. S phase: Progression through S phase involves cyclin E–Cdk2 and cyclin A–Cdk2 complexes. PER1 is linked to cyclin E–Cdk2 regulation, while REV-ERBα modulates cyclin A–Cdk2 activity, contributing to S-phase control. G2 phase: Transition into mitosis is coordinated by cyclin B–Cdk1. BMAL1/CLOCK regulate WEE1, which in turn modulates cyclin B–Cdk1 activity. CRY1 and PER1 influence WEE1, further integrating circadian control at the G2 checkpoint. M phase and G2/M checkpoint: Circadian components intersect with DDR pathways, including PER2–CHK2, CRY1–TIM–ATR–CHK1, and PER1–TIM–ATM–CHK2, which modulate cyclin B–Cdk1-dependent mitotic progression. External cues, such as DD are depicted as additional modulators at this stage. ATR, ATR serine/threonine kinase; ATM, ATM serine/threonine kinase; BMAL1, brain and muscle ARNT-like protein1; CCD, chronic circadian disruption; CDK, cyclin-dependent kinase; CHK1/2, checkpoint kinase1/2; Cdk1/2/4/6, cyclin dependent kinase 1/2/4/6; CLOCK, circadian locomotor output cycles kaput; CRY1, cryptochrome1; CJL, chronic jet-lag; DD, constant dark; PER1/2, period circadian regulator1/2; RORα, retinoic acid receptor-related orphan receptorα; REV-ERBα, nuclear receptor subfamily 1 group d member; TIM, timeless; WEE1, G2 checkpoint kinase.

Numerous parallels are shared among the circadian regulatory system and cellular division process as biological rhythms within dividing cells with each featuring alternating periods of activation and suppression. Studies show that circadian rhythms impact all steps in the cell division process. For example, during the G1 period, REV-ERBα and RORα facilitate the course of the cellular division process via suppress the transcription of p21cip199. In contrast, PER1 and TIMELESS hinder the G1-S transition by linking up with ATM and CHK2, leading to stagnation of the cell cycle100. CRY1 facilitates the course of the cell cycle by suppressing the special kinase (WEE1), regulating the G2-M checkpoint, which promotes entry into mitosis101. In addition, CRY1 aids in the cycle course by repressing WEE1, a kinase responsible for controlling the G2-M checkpoint, thus facilitating entry into mitosis.

The heterodimer of CLOCK and BMAL1 influences the rhythmic transcription of WEE1 and WEE2, effectively managing cell cycle arrest101. It has been proposed that the CLOCK–BMAL1 heterodimer influences cell cycle progression by regulating cyclin B1 expression, particularly during the G2/M transition102. Conversely, various analyses have revealed that CRY1 limits mitosis by influencing the G2-M transition through mediation of ATM, ATR, and CHK1. This regulation occurs via the interaction with the TIMELESS (TIM) in a manner governed by regulating circadian rhythms103. Based on the literature discussed above, circadian regulators are critically involved in modulating G1/S and G2/M phase transitions of the cell cycle with the effects varying depending on the context and the phase of the circadian rhythm.

External intervention and CLJ induced disruption of rhythmic expression patterns of the clock and cyclin genes in the liver, resulting in elevated levels of CcnA2 in tumors, as well as a reduction in p21WAF/CIP1 expression, all of which cause a proliferative phenotype74. A study in U2OS cells showed that chronic circadian desynchrony (CCD) [serial 8-h advances of the dexamethasone (dex) treatment cycle every 2 d], a substitution of CJL, displayed upregulation of G1/S phase transition genes, including Myc and cyclin D1/3, accompanied by enhanced phosphorylation of the retinoblastoma protein by CDK4/6 with increased G1-S progression104. With respect to clock genes, the anti-tumor effect of BMAL1 in GBM is associated with reduced migratory and invasive capacities that is mediated by decreased cyclin B1 expression54. PER1105 and PER2106 are of vital importance in controlling the cell cycle process and ensuring equilibrium between cell proliferation and apoptosis by influencing the cyclin/CDK/CKI network involved in the cell cycle107. SR9011, an REV-ERB agonist, impedes breast cancer cell proliferation by targeting cyclin A (CCNA2) and arresting the cell cycle prior to the mitotic phase108. In summary, circadian–cell cycle interactions critically shape tumorigenic potential through complex regulatory mechanisms that likely contribute significantly to the effects of diurnal disruption on tumor progression. New research aims to connect these molecular insights to the mechanisms underlying tumor cell proliferation driven by circadian disruption, providing a clearer understanding of the role in cancer progression.

Perspective

The circadian clock regulates 24-h circadian rhythms of numerous physiologic activities through modulation of gene expression. Disruption of circadian rhythms appears to be involved in tumor metastasis, potentially through dysregulation of key biological processes, such as cell growth, tissue homeostasis, metabolism, and response to stimuli. Tumor metastasis is heavily influenced by the complex and dynamic TME where the tumor develops, invades, and spreads. Highly plastic cancer-resident stem cell populations occupying these specialized TMEs are strongly influenced by local niche signals to facilitate invasion and metastasis. Tumor-associated immune cells, stromal niches, and CSCs display robust and self-automatic rhythmic oscillations under the control of the circadian clock. Herein we discuss the diverse circadian clock signals that support the TME in the context of different stages of tumor metastasis from primary tumors to distant organs, encompassing invasion, intravasation, circulation, extravasation, cell cycle progression, immune response, and angiogenesis. We outline recent advances that suggest circadian disruption that may influence tumor metastasis and offer potential avenues for therapeutic intervention.

Although epidemiologic and experimental studies have firmly established the association between circadian disruption and tumor metastasis, the molecular intricacies within the TME remain inadequately elucidated. To better illustrate the chronobiology reporting standards in circadian research, we have summarized relevant guidelines from previous studies and presented the guidelines in Figure 6. This review synthesizes current evidence on how circadian disruption-mediated through environmental perturbations (chronic jet lag/CJL, light-at-night/LAN, long days/LL, constant darkness/DD, and shift work/SD) and core clock gene dysregulation-orchestrates metastatic dissemination via TME remodeling. For example, BMAL1 suppresses the migratory and invasive potential of U87MG, lung, and glioma cancer cells55. In contrast, BMAL1 facilitates breast cancer cell metastasis by upregulating MMP9 expression58. Core clock components exhibit context-dependent metastatic regulation, necessitating lineage-specific analysis. Given the context-dependent nature of circadian regulation, the effects of core clock genes on tumor progression appear to vary across experimental models, temporal paradigms, and tumor backgrounds. Differences in sampling time, cell or animal models, and the intrinsic metabolic or immunologic characteristics of each tumor type may underlie the observed inconsistencies among studies. Future work should therefore focus on delineating tumor- and stage-specific mechanisms by which circadian genes influence cancer behavior, as well as developing standardized time-resolved experimental designs to improve the comparability and reproducibility of circadian oncology research109.

Chronobiology reporting standards in circadian research. Schematic overview of key methodologic parameters that should be reported in circadian studies, including Zeitgeber time definition, light–dark cycle conditions, gender and age of experimental subjects, jet lag or chronic circadian disruption paradigms, and time-aware statistical methods.
Figure 6

Chronobiology reporting standards in circadian research. Schematic overview of key methodologic parameters that should be reported in circadian studies, including Zeitgeber time definition, light–dark cycle conditions, gender and age of experimental subjects, jet lag or chronic circadian disruption paradigms, and time-aware statistical methods.

However, regulation of circadian clock cells in the TME has not been fully discussed, which leaves critical knowledge gaps in TME chronobiology. For example, how do central SCN clocks entrain pericyte-endothelial oscillators-especially when pericyte ablation extinguishes endothelial rhythms? The diurnal activity peaks of CAFs, platelets, and tumor-derived exosomes remain unmapped. Neutrophil TEM peaks at ZT14, yet CAF-collagen remodeling timing is unknown.

Moreover, the metastasis-phase-specific roles remain unclear. Clock control over circulating CTC clusters during vascular transit requires intravital imaging validation. To advance this field, we propose spatiotemporal multi-omics, as follows: combining time-series scRNA-seq with circadian proteomics of TME components (e.g., ECM-bound TIMP1 diurnal turnover); microfluidic TME-on-Chip, mimicking rhythmic interstitial flow to test chronopharmacology; and stromal-targeted chronotherapy, exploiting CDK4/6 inhibitor efficacy windows aligned with CAF activation cycles. While circadian regulation of TME dynamics is recognized as a metastasis “gatekeeper,” resolving the molecular spatiotemporal map of stromal-tumor interactions will unlock chronotherapeutic strategies-potentially halting metastasis through time-targeted disruption of TME remodeling.

In the pharmacologic domain, several small-molecule modulators targeting core circadian regulators are currently under exploration. Representative examples include the BMAL1-targeting compound [core circadian modulator (CCM)], which binds to the PAS-B domain of BMAL1 to fine-tune transcriptional activity and suppress tumor growth in experimental models110 and the CRY1-selective molecule. M47, which destabilizes CRY1 and has been shown to prolong lifespan in p53-knockout tumor-prone mice111. In addition, the REV-ERB agonists, SR9009 and SR9011, have been reported to modulate circadian and metabolic pathways in preclinical studies66, although limited pharmacologic specificity and regulatory restrictions constrain translational applicability. While most of these compounds remain in early mechanistic stages, continued progress in clock-directed pharmacology is expected to expand therapeutic opportunities in circadian-based precision oncology. Despite increasing evidence linking circadian disruption to cancer progression and therapeutic response, standardized clinical frameworks for time-dependent sampling or chronotherapy trials remain lacking. Current oncology studies rarely report biological sample timing, treatment delivery phase, or patient chronotype, underscoring the need for harmonized chronobiology guidelines. Future efforts should aim to establish practical recommendations for biospecimen collection windows (e.g., CTCs or plasma biomarkers) and explore feasible time-stratified or time-randomized clinical trial designs for chemotherapy and immunotherapy. Developing such translational standards will be essential for integrating circadian principles into precision oncology.

In summary, numerous studies have explored how clock genes may regulate the TME, suggesting a potential role in tumor metastasis. However, details regarding the molecular mechanisms underlying these remain open. We expect that corollary studies will deepen our comprehension of these complex interactions, facilitating the creation of novel strategies for cancer therapy.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived the structure of the manuscript: Jie Wang, Hao Pan, Yu Wang.

Contributed figures: Hao Pan, Xuan Wang.

Wrote the paper: Jie Wang, Hao Pan, Xuan Wang, Yiwen Huang, Hejin Lai, Yizhou Liu.

Revised the paper: Yu Wang, Ning Pu and Zhimin Fei.

  • Received September 2, 2025.
  • Accepted February 25, 2026.

References

  1. 1.↵
    2. Pundir M,
    3. Papagerakis S,
    4. De Rosa MC,
    5. Chronis N,
    6. Kurabayashi K,
    7. Abdulmawjood S, et al.
    Emerging biotechnologies for evaluating disruption of stress, sleep, and circadian rhythm mechanism using aptamer-based detection of salivary biomarkers. Biotechnol Adv. 2022; 59: 107961.
  2. 2.↵
    2. Gerhart-Hines Z,
    3. Lazar MA.
    Rev-erbα and the circadian transcriptional regulation of metabolism. Diabetes Obes Metab. 2015; 17: 12–6.
    OpenUrlPubMed
  3. 3.↵
    2. Mohawk JA,
    3. Green CB,
    4. Takahashi JS.
    Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012; 35: 445–62.
    OpenUrlCrossRefPubMed
  4. 4.↵
    2. Diamantopoulou Z,
    3. Castro-Giner F,
    4. Schwab FD,
    5. Foerster C,
    6. Saini M,
    7. Budinjas S, et al.
    The metastatic spread of breast cancer accelerates during sleep. Nature. 2022; 607: 156–62.
    OpenUrlCrossRefPubMed
  5. 5.↵
    2. Numata M,
    3. Hirano A,
    4. Yamamoto Y,
    5. Yasuda M,
    6. Miura N,
    7. Sayama K, et al.
    Metastasis of breast cancer promoted by circadian rhythm disruption due to light/dark shift and its prevention by dietary quercetin in mice. J Circadian Rhythms. 2021; 19: 2.
    OpenUrlPubMed
  6. 6.↵
    2. Wang Y,
    3. Sun N,
    4. Lu C,
    5. Bei Y,
    6. Qian R,
    7. Hua L.
    Upregulation of circadian gene ‘hClock’ contribution to metastasis of colorectal cancer. Int J Oncol. 2017; 50: 2191–9.
    OpenUrlPubMed
  7. 7.↵
    2. Liu K,
    3. Cui JJ,
    4. Zhan Y,
    5. Ouyang QY,
    6. Lu QS,
    7. Yang DH, et al.
    Reprogramming the tumor microenvironment by genome editing for precision cancer therapy. Mol Cancer. 2022; 21: 98.
    OpenUrlPubMed
  8. 8.↵
    2. Bose S,
    3. Saha P,
    4. Chatterjee B,
    5. Srivastava AK.
    Chemokines driven ovarian cancer progression, metastasis and chemoresistance: potential pharmacological targets for cancer therapy. Semin Cancer Biol. 2022; 86: 568–79.
    OpenUrlPubMed
  9. 9.↵
    2. Quail DF,
    3. Joyce JA.
    Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19: 1423–37.
    OpenUrlCrossRefPubMed
  10. 10.↵
    2. Singleton DC,
    3. Macann A,
    4. Wilson WR.
    Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol. 2021; 18: 751–72.
    OpenUrlCrossRefPubMed
  11. 11.↵
    2. Wang Y,
    3. Guo H,
    4. He F.
    Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets. Cancer Metastasis Rev. 2023; 42: 297–322.
    OpenUrlPubMed
  12. 12.↵
    2. Wang Y,
    3. Narasimamurthy R,
    4. Qu M,
    5. Shi N,
    6. Guo H,
    7. Xue Y, et al.
    Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis. Nat Cancer. 2024; 5: 546–56.
    OpenUrlPubMed
  13. 13.↵
    2. Touitou Y,
    3. Reinberg A,
    4. Touitou D.
    Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: health impacts and mechanisms of circadian disruption. Life Sci. 2017; 173: 94–106.
    OpenUrlCrossRefPubMed
  14. 14.↵
    2. Xiao Q,
    3. James P,
    4. Breheny P,
    5. Jia P,
    6. Park Y,
    7. Zhang D, et al.
    Outdoor light at night and postmenopausal breast cancer risk in the NIH-AARP diet and health study. Int J Cancer. 2020; 147: 2363–72.
    OpenUrlPubMed
  15. 15.↵
    2. Clarke RB,
    3. Amini H,
    4. James P,
    5. von Euler-Chelpin M,
    6. Jørgensen JT,
    7. Mehta A, et al.
    Outdoor light at night and breast cancer incidence in the Danish Nurse Cohort. Environ Res. 2021; 194: 110631.
  16. 16.↵
    2. Kim TW,
    3. Jeong JH,
    4. Hong SC.
    The impact of sleep and circadian disturbance on hormones and metabolism. Int J Endocrinol. 2015; 2015: 591729.
  17. 17.↵
    2. Zeitzer JM,
    3. Nouriani B,
    4. Rissling MB,
    5. Sledge GW,
    6. Kaplan KA,
    7. Aasly L, et al.
    Aberrant nocturnal cortisol and disease progression in women with breast cancer. Breast Cancer Res Treat. 2016; 158: 43–50.
    OpenUrlPubMed
  18. 18.↵
    2. Starreveld DEJ,
    3. Habers GEA,
    4. Valdimarsdottir HB,
    5. Kessels R,
    6. Daniëls LA,
    7. van Leeuwen FE, et al.
    Cancer-related fatigue in relation to chronotype and sleep quality in (non-)Hodgkin lymphoma survivors. J Biol Rhythms. 2021; 36: 71–83.
    OpenUrlPubMed
  19. 19.↵
    2. Cash E,
    3. Duck CR,
    4. Brinkman C,
    5. Rebholz W,
    6. Albert C,
    7. Worthen M, et al.
    Depressive symptoms and actigraphy-measured circadian disruption predict head and neck cancer survival. Psychooncology. 2018; 27: 2500–7.
    OpenUrlPubMed
  20. 20.↵
    2. Zhang J,
    3. Lv H,
    4. Ji M,
    5. Wang Z,
    6. Wu W.
    Low circadian clock genes expression in cancers: a meta-analysis of its association with clinicopathological features and prognosis. PLoS One. 2020; 15: e0233508.
  21. 21.↵
    2. Kuo SJ,
    3. Chen ST,
    4. Yeh KT,
    5. Hou MF,
    6. Chang YS,
    7. Hsu NC, et al.
    Disturbance of circadian gene expression in breast cancer. Virchows Arch. 2009; 454: 467–74.
    OpenUrlCrossRefPubMed
  22. 22.↵
    2. Cadenas C,
    3. van de Sandt L,
    4. Edlund K,
    5. Lohr M,
    6. Hellwig B,
    7. Marchan R, et al.
    Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle. 2014; 13: 3282–91.
    OpenUrlCrossRefPubMed
  23. 23.↵
    2. Yi H,
    3. Liao ZW,
    4. Chen JJ,
    5. Shi XY,
    6. Chen GL,
    7. Wu GT, et al.
    Genome variation in colorectal cancer patient with liver metastasis measured by whole-exome sequencing. J Gastrointest Oncol. 2021; 12: 507–15.
    OpenUrlPubMed
  24. 24.↵
    2. Oshima T,
    3. Takenoshita S,
    4. Akaike M,
    5. Kunisaki C,
    6. Fujii S,
    7. Nozaki A, et al.
    Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer. Oncol Rep. 2011; 25: 1439–46.
    OpenUrlPubMed
  25. 25.↵
    2. Mazzoccoli G,
    3. Pazienza V,
    4. Panza A,
    5. Valvano MR,
    6. Benegiamo G,
    7. Vinciguerra M, et al.
    ARNTL2 and SERPINE1: potential biomarkers for tumor aggressiveness in colorectal cancer. J Cancer Res Clin Oncol. 2012; 138: 501–11.
    OpenUrlCrossRefPubMed
  26. 26.↵
    2. He QY,
    3. Jin F,
    4. Li YY,
    5. Wu WL,
    6. Long JH,
    7. Luo XL, et al.
    Prognostic significance of downregulated BMAL1 and upregulated Ki-67 proteins in nasopharyngeal carcinoma. Chronobiol Int. 2018; 35: 348–57.
    OpenUrlPubMed
  27. 27.↵
    2. Cai YD,
    3. Chiu JC.
    Timeless in animal circadian clocks and beyond. FEBS J. 2022; 289: 6559–75.
    OpenUrlCrossRefPubMed
  28. 28.↵
    2. Wang X,
    3. Wang N,
    4. Wei X,
    5. Yu H,
    6. Wang Z.
    REV-ERBα reduction is associated with clinicopathological features and prognosis in human gastric cancer. Oncol Lett. 2018; 16: 1499–506.
    OpenUrlPubMed
  29. 29.↵
    2. Chen J,
    3. Liu A,
    4. Lin Z,
    5. Wang B,
    6. Chai X,
    7. Chen S, et al.
    Downregulation of the circadian rhythm regulator HLF promotes multiple-organ distant metastases in non-small cell lung cancer through PPAR/NF-κb signaling. Cancer Lett. 2020; 482: 56–71.
    OpenUrlPubMed
  30. 30.↵
    2. Wang Y,
    3. Ding Y,
    4. Guo N,
    5. Wang S.
    MDSCs: key criminals of tumor pre-metastatic niche formation. Front Immunol. 2019; 10: 172.
    OpenUrlCrossRefPubMed
  31. 31.↵
    2. Scheiermann C,
    3. Gibbs J,
    4. Ince L,
    5. Loudon A.
    Clocking in to immunity. Nat Rev Immunol. 2018; 18: 423–37.
    OpenUrlCrossRefPubMed
  32. 32.↵
    2. Perfilyeva YV,
    3. Abdolla N,
    4. Ostapchuk YO,
    5. Tleulieva R,
    6. Krasnoshtanov VC,
    7. Belyaev NN.
    Expansion of CD11b+Ly6Ghigh and CD11b+CD49d+ myeloid cells with suppressive potential in mice with chronic inflammation and light-at-night-induced circadian disruption. Inflamm Res. 2017; 66: 711–24.
    OpenUrlPubMed
  33. 33.↵
    2. Hadadi E,
    3. Taylor W,
    4. Li XM,
    5. Aslan Y,
    6. Villote M,
    7. Rivière J, et al.
    Chronic circadian disruption modulates breast cancer stemness and immune microenvironment to drive metastasis in mice. Nat Commun. 2020; 11: 3193.
    OpenUrlCrossRefPubMed
  34. 34.↵
    2. Zeng X,
    3. Liang C,
    4. Yao J.
    Chronic shift-lag promotes NK cell ageing and impairs immunosurveillance in mice by decreasing the expression of CD122. J Cell Mol Med. 2020; 24: 14583–95.
    OpenUrlPubMed
  35. 35.↵
    2. Logan RW,
    3. Zhang C,
    4. Murugan S,
    5. O’Connell S,
    6. Levitt D,
    7. Rosenwasser AM, et al.
    Chronic shift-lag alters the circadian clock of NK cells and promotes lung cancer growth in rats. J Immunol. 2012; 188: 2583–91.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    2. Tian R,
    3. Li Y,
    4. Shu M.
    Circadian regulation patterns with distinct immune landscapes in gliomas aid in the development of a risk model to predict prognosis and therapeutic response. Front Immunol. 2021; 12: 797450.
  37. 37.↵
    2. de Assis LVM,
    3. Kinker GS,
    4. Moraes MN,
    5. Markus RP,
    6. Fernandes PA,
    7. Castrucci AML.
    Expression of the circadian clock gene BMAL1 positively correlates with antitumor immunity and patient survival in metastatic melanoma. Front Oncol. 2018; 8: 185.
    OpenUrlPubMed
  38. 38.↵
    2. Shaashua L,
    3. Mayer S,
    4. Lior C,
    5. Lavon H,
    6. Novoselsky A,
    7. Scherz-Shouval R.
    Stromal expression of the core clock gene period 2 is essential for tumor initiation and metastatic colonization. Front Cell Dev Biol. 2020; 8: 587697.
  39. 39.↵
    2. Lee IK,
    3. Song H,
    4. Kim H,
    5. Kim IS,
    6. Tran NL,
    7. Kim SH, et al.
    RORα regulates cholesterol metabolism of CD8+ T cells for anticancer immunity. Cancers. 2020; 12: 1733.
    OpenUrlPubMed
  40. 40.↵
    2. Park SC,
    3. Park IG,
    4. Kim H,
    5. Lee JM.
    N-terminal domain mediated regulation of RORα1 inhibits invasive growth in prostate cancer. Int J Mol Sci. 2019; 20: 1684.
    OpenUrlPubMed
  41. 41.↵
    2. Yu X,
    3. Rollins D,
    4. Ruhn KA,
    5. Stubblefield JJ,
    6. Green CB,
    7. Kashiwada M, et al.
    TH17 cell differentiation is regulated by the circadian clock. Science. 2013; 342: 727–30.
    OpenUrlAbstract/FREE Full Text
  42. 42.↵
    2. Hu X,
    3. Liu X,
    4. Moisan J,
    5. Wang Y,
    6. Lesch CA,
    7. Spooner C, et al.
    Synthetic RORγ agonists regulate multiple pathways to enhance antitumor immunity. Oncoimmunology. 2016; 5: e1254854.
  43. 43.↵
    2. Teleanu RI,
    3. Chircov C,
    4. Grumezescu AM,
    5. Teleanu DM.
    Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med. 2019; 9: 84.
    OpenUrlPubMed
  44. 44.↵
    2. Mastrullo V,
    3. Cathery W,
    4. Velliou E,
    5. Madeddu P,
    6. Campagnolo P.
    Angiogenesis in tissue engineering: as nature intended? Front Bioeng Biotechnol. 2020; 8: 188.
    OpenUrlPubMed
  45. 45.↵
    2. Takaguri A,
    3. Sasano J,
    4. Akihiro O,
    5. Satoh K.
    The role of circadian clock gene BMAL1 in vascular proliferation. Eur J Pharmacol. 2020; 872: 172924.
  46. 46.↵
    2. Haus E,
    3. Dumitriu L,
    4. Nicolau GY,
    5. Bologa S,
    6. Sackett-Lundeen L.
    Circadian rhythms of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, and melatonin in women with breast cancer. Chronobiol Int. 2001; 18: 709–27.
    OpenUrlCrossRefPubMed
  47. 47.↵
    2. Yasuniwa Y,
    3. Izumi H,
    4. Wang KY,
    5. Shimajiri S,
    6. Sasaguri Y,
    7. Kawai K, et al.
    Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway. PLoS One. 2010; 5: e15330.
  48. 48.↵
    2. Wood PA,
    3. Du-Quiton J,
    4. You S,
    5. Hrushesky WJ.
    Circadian clock coordinates cancer cell cycle progression, thymidylate synthase, and 5-fluorouracil therapeutic index. Mol Cancer Ther. 2006; 5: 2023–33.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    2. Wang CY,
    3. Wen MS,
    4. Wang HW,
    5. Hsieh IC,
    6. Li Y,
    7. Liu PY, et al.
    Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2. Circulation. 2008; 118: 2166–73.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    2. Miyazaki K,
    3. Wakabayashi M,
    4. Hara Y,
    5. Ishida N.
    Tumor growth suppression in vivo by overexpression of the circadian component, PER2. Genes Cells. 2010; 15: 351–8.
    OpenUrlCrossRefPubMed
  51. 51.↵
    2. Besnard S,
    3. Silvestre JS,
    4. Duriez M,
    5. Bakouche J,
    6. Lemaigre-Dubreuil Y,
    7. Mariani J, et al.
    Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha. Circ Res. 2001; 89: 1209–15.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    2. Xu L,
    3. Liu Y,
    4. Cheng Q,
    5. Shen Y,
    6. Yuan Y,
    7. Jiang X, et al.
    Bmal1 downregulation worsens critical limb ischemia by promoting inflammation and impairing angiogenesis. Front Cardiovasc Med. 2021; 8: 712903.
  53. 53.↵
    2. Pastushenko I,
    3. Blanpain C.
    EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019; 29: 212–26.
    OpenUrlCrossRefPubMed
  54. 54.↵
    2. Gwon DH,
    3. Lee WY,
    4. Shin N,
    5. Kim SI,
    6. Jeong K,
    7. Lee WH, et al.
    BMAL1 suppresses proliferation, migration, and invasion of U87MG cells by downregulating cyclin B1, phospho-AKT, and metalloproteinase-9. Int J Mol Sci. 2020; 21: 2352.
    OpenUrlPubMed
  55. 55.↵
    2. Jung CH,
    3. Kim EM,
    4. Park JK,
    5. Hwang SG,
    6. Moon SK,
    7. Kim WJ, et al.
    BMAL1 suppresses cancer cell invasion by blocking the phosphoinositide 3-kinase-Akt-MMP-2 signaling pathway. Oncol Rep. 2013; 29: 2109–13.
    OpenUrlCrossRefPubMed
  56. 56.↵
    2. Zhu M,
    3. Tang H,
    4. Tang X,
    5. Ma X,
    6. Guo D,
    7. Chen F.
    BMAL1 suppresses ROS-induced endothelial-to-mesenchymal transition and atherosclerosis plaque progression via BMP signaling. Am J Transl Res. 2018; 10: 3150–61.
    OpenUrlPubMed
  57. 57.↵
    2. Li Y,
    3. Basti A,
    4. Yalçin M,
    5. Relógio A.
    Circadian dysregulation of the TGFβ/SMAD4 pathway modulates metastatic properties and cell fate decisions in pancreatic cancer cells. iScience. 2020; 23: 101551.
  58. 58.↵
    2. Wang J,
    3. Li S,
    4. Li X,
    5. Li B,
    6. Li Y,
    7. Xia K, et al.
    Circadian protein BMAL1 promotes breast cancer cell invasion and metastasis by up-regulating matrix metalloproteinase9 expression. Cancer Cell Int. 2019; 19: 182.
    OpenUrlPubMed
  59. 59.↵
    2. Ma TJ,
    3. Zhang ZW,
    4. Lu YL,
    5. Zhang YY,
    6. Tao DC,
    7. Liu YQ, et al.
    CLOCK and BMAL1 stabilize and activate RHOA to promote F-actin formation in cancer cells. Exp Mol Med. 2018; 50: 1–15.
    OpenUrlCrossRefPubMed
  60. 60.↵
    2. Hwang-Verslues WW,
    3. Chang PH,
    4. Jeng YM,
    5. Kuo WH,
    6. Chiang PH,
    7. Chang YC, et al.
    Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy. Proc Natl Acad Sci U S A. 2013; 110: 12331–6.
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    2. Wang D,
    3. Fu L,
    4. Sun H,
    5. Guo L,
    6. DuBois RN.
    Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology. 2015; 149: 1884–95.e4.
    OpenUrlCrossRefPubMed
  62. 62.
    2. Shibue T,
    3. Weinberg RA.
    EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017; 14: 611–29.
    OpenUrlCrossRefPubMed
  63. 63.↵
    2. Yang L,
    3. Shi P,
    4. Zhao G,
    5. Xu J,
    6. Peng W,
    7. Zhang J, et al.
    Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020; 5: 8.
    OpenUrlPubMed
  64. 64.↵
    2. Chen P,
    3. Hsu WH,
    4. Chang A,
    5. Tan Z,
    6. Lan Z,
    7. Zhou A, et al.
    Circadian regulator CLOCK recruits immune-suppressive microglia into the GBM tumor microenvironment. Cancer Discov. 2020; 10: 371–81.
    OpenUrlAbstract/FREE Full Text
  65. 65.↵
    2. Xuan W,
    3. Hsu WH,
    4. Khan F,
    5. Dunterman M,
    6. Pang L,
    7. Wainwright DA, et al.
    Circadian regulator CLOCK drives immunosuppression in glioblastoma. Cancer Immunol Res. 2022; 10: 770–84.
    OpenUrlCrossRefPubMed
  66. 66.↵
    2. Puram RV,
    3. Kowalczyk MS,
    4. de Boer CG,
    5. Schneider RK,
    6. Miller PG,
    7. McConkey M, et al.
    Core circadian clock genes regulate leukemia stem cells in AML. Cell. 2016; 165: 303–16.
    OpenUrlCrossRefPubMed
  67. 67.↵
    2. Dong Z,
    3. Zhang G,
    4. Qu M,
    5. Gimple RC,
    6. Wu Q,
    7. Qiu Z, et al.
    Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 2019; 9: 1556–73.
    OpenUrlAbstract/FREE Full Text
  68. 68.↵
    2. De A,
    3. Beligala DH,
    4. Sharma VP,
    5. Burgos CA,
    6. Lee AM,
    7. Geusz ME.
    Cancer stem cell generation during epithelial-mesenchymal transition is temporally gated by intrinsic circadian clocks. Clin Exp Metastasis. 2020; 37: 617–35.
    OpenUrlPubMed
  69. 69.↵
    2. Li Q,
    3. Xia D,
    4. Wang Z,
    5. Liu B,
    6. Zhang J,
    7. Peng P, et al.
    Circadian rhythm gene PER3 negatively regulates stemness of prostate cancer stem cells via WNT/β-catenin signaling in tumor microenvironment. Front Cell Dev Biol. 2021; 9: 656981.
  70. 70.↵
    2. Zeeshan R,
    3. Mutahir Z.
    Cancer metastasis – tricks of the trade. Bosn J Basic Med Sci. 2017; 17: 172–82.
    OpenUrlPubMed
  71. 71.↵
    2. Fu LQ,
    3. Du WL,
    4. Cai MH,
    5. Yao JY,
    6. Zhao YY,
    7. Mou XZ.
    The roles of tumor-associated macrophages in tumor angiogenesis and metastasis. Cell Immunol. 2020; 353: 104119.
  72. 72.↵
    2. Sharma VP,
    3. Tang B,
    4. Wang Y,
    5. Duran CL,
    6. Karagiannis GS,
    7. Xue EA, et al.
    Live tumor imaging shows macrophage induction and TMEM-mediated enrichment of cancer stem cells during metastatic dissemination. Nat Commun. 2021; 12: 7300.
    OpenUrlCrossRefPubMed
  73. 73.↵
    2. Sun Z,
    3. Li L,
    4. Yan Z,
    5. Zhang L,
    6. Zang G,
    7. Qian Y, et al.
    Circadian rhythm disorders elevate macrophages cytokines release and promote multiple tissues/organs dysfunction in mice. Physiol Behav. 2022; 249: 113772.
  74. 74.↵
    2. Aiello I,
    3. Mul Fedele ML,
    4. Román F,
    5. Marpegan L,
    6. Caldart C,
    7. Chiesa JJ, et al.
    Circadian disruption promotes tumor-immune microenvironment remodeling favoring tumor cell proliferation. Sci Adv. 2020; 6: eaaz4530.
  75. 75.↵
    2. Curtis AM,
    3. Fagundes CT,
    4. Yang G,
    5. Palsson-McDermott EM,
    6. Wochal P,
    7. McGettrick AF, et al.
    Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc Natl Acad Sci U S A. 2015; 112: 7231–6.
    OpenUrlAbstract/FREE Full Text
  76. 76.↵
    2. Gowda P,
    3. Lathoria K,
    4. Sharma S,
    5. Patrick S,
    6. Umdor SB,
    7. Sen E.
    Rewiring of lactate-interleukin-1β autoregulatory loop with clock-Bmal1: a feed-forward circuit in glioma. Mol Cell Biol. 2021; 41: e0044920.
  77. 77.↵
    2. Alexander RK,
    3. Liou YH,
    4. Knudsen NH,
    5. Starost KA,
    6. Xu C,
    7. Hyde AL, et al.
    Bmal1 integrates mitochondrial metabolism and macrophage activation. Elife. 2020; 9: e54090.
  78. 78.↵
    2. Sato S,
    3. Sakurai T,
    4. Ogasawara J,
    5. Takahashi M,
    6. Izawa T,
    7. Imaizumi K, et al.
    A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression. J Immunol. 2014; 192: 407–17.
    OpenUrlAbstract/FREE Full Text
  79. 79.↵
    2. Hams E,
    3. Roberts J,
    4. Bermingham R,
    5. Fallon PG.
    Functions for retinoic acid-related orphan receptor alpha (RORα) in the activation of macrophages during lipopolysaccharide-induced septic shock. Front Immunol. 2021; 12: 647329.
  80. 80.↵
    2. Haemmerle M,
    3. Stone RL,
    4. Menter DG,
    5. Afshar-Kharghan V,
    6. Sood AK.
    The platelet lifeline to cancer: challenges and opportunities. Cancer Cell. 2018; 33: 965–83.
    OpenUrlCrossRefPubMed
  81. 81.↵
    2. Paiva B,
    3. Paino T,
    4. Sayagues JM,
    5. Garayoa M,
    6. San-Segundo L,
    7. Martín M, et al.
    Detailed characterization of multiple myeloma circulating tumor cells shows unique phenotypic, cytogenetic, functional, and circadian distribution profile. Blood. 2013; 122: 3591–8.
    OpenUrlAbstract/FREE Full Text
  82. 82.↵
    2. Zhu X,
    3. Suo Y,
    4. Fu Y,
    5. Zhang F,
    6. Ding N,
    7. Pang K, et al.
    In vivo flow cytometry reveals a circadian rhythm of circulating tumor cells. Light Sci Appl. 2021; 10: 110.
    OpenUrlPubMed
  83. 83.↵
    2. Tracey CJ,
    3. Pan X,
    4. Catterson JH,
    5. Harmar AJ,
    6. Hussain MM,
    7. Hartley PS.
    Diurnal expression of the thrombopoietin gene is regulated by CLOCK. J Thromb Haemost. 2012; 10: 662–9.
    OpenUrlCrossRefPubMed
  84. 84.↵
    2. Moustafa A.
    Chronic exposure to continuous brightness or darkness modulates immune responses and ameliorates the antioxidant enzyme system in male rats. Front Vet Sci. 2021; 8: 621188.
  85. 85.↵
    2. Krüger-Genge A,
    3. Blocki A,
    4. Franke RP,
    5. Jung F.
    Vascular endothelial cell biology: an update. Int J Mol Sci. 2019; 20: 4411.
    OpenUrlCrossRefPubMed
  86. 86.↵
    2. Bain AR,
    3. Weil BR,
    4. Diehl KJ,
    5. Greiner JJ,
    6. Stauffer BL,
    7. DeSouza CA.
    Insufficient sleep is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation. Atherosclerosis. 2017; 265: 41–6.
    OpenUrlPubMed
  87. 87.↵
    2. McAlpine CS,
    3. Swirski FK.
    Circadian influence on metabolism and inflammation in atherosclerosis. Circ Res. 2016; 119: 131–41.
    OpenUrlAbstract/FREE Full Text
  88. 88.↵
    2. Gao Y,
    3. Meng D,
    4. Sun N,
    5. Zhu Z,
    6. Zhao R,
    7. Lu C, et al.
    Clock upregulates intercellular adhesion molecule-1 expression and promotes mononuclear cells adhesion to endothelial cells. Biochem Biophys Res Commun. 2014; 443: 586–91.
    OpenUrlCrossRefPubMed
  89. 89.↵
    2. He W,
    3. Holtkamp S,
    4. Hergenhan SM,
    5. Kraus K,
    6. de Juan A,
    7. Weber J, et al.
    Circadian expression of migratory factors establishes lineage-specific signatures that guide the homing of leukocyte subsets to tissues. Immunity. 2018; 49: 1175–90.e7.
    OpenUrlCrossRefPubMed
  90. 90.↵
    2. Takeda N,
    3. Maemura K.
    Circadian clock and the onset of cardiovascular events. Hypertens Res. 2016; 39: 383–90.
    OpenUrlCrossRefPubMed
  91. 91.↵
    2. Rodrigo GC,
    3. Denniff M.
    Time-of-day variation in vascular function. Exp Physiol. 2016; 101: 1030–4.
    OpenUrlPubMed
  92. 92.↵
    2. Zhang SL,
    3. Lahens NF,
    4. Yue Z,
    5. Arnold DM,
    6. Pakstis PP,
    7. Schwarz JE, et al.
    A circadian clock regulates efflux by the blood-brain barrier in mice and human cells. Nat Commun. 2021; 12: 617.
    OpenUrlCrossRefPubMed
  93. 93.↵
    2. Mastrullo V,
    3. van der Veen DR,
    4. Gupta P,
    5. Matos RS,
    6. Johnston JD,
    7. McVey JH, et al.
    Pericytes’ circadian clock affects endothelial cells’ synchronization and angiogenesis in a 3D tissue engineered scaffold. Front Pharmacol. 2022; 13: 867070.
  94. 94.↵
    2. Khalyfa A,
    3. Poroyko VA,
    4. Qiao Z,
    5. Gileles-Hillel A,
    6. Khalyfa AA,
    7. Akbarpour M, et al.
    Exosomes and metabolic function in mice exposed to alternating dark-light cycles mimicking night shift work schedules. Front Physiol. 2017; 8: 882.
    OpenUrlCrossRefPubMed
  95. 95.↵
    2. Yeung CC,
    3. Dondelinger F,
    4. Schoof EM,
    5. Georg B,
    6. Lu Y,
    7. Zheng Z, et al.
    Circadian regulation of protein cargo in extracellular vesicles. Sci Adv. 2022; 8: eabc9061.
  96. 96.↵
    2. Dong P,
    3. Wang Y,
    4. Liu Y,
    5. Zhu C,
    6. Lin J,
    7. Qian R, et al.
    BMAL1 induces colorectal cancer metastasis by stimulating exosome secretion. Mol Biol Rep. 2022; 49: 373–84.
    OpenUrlPubMed
  97. 97.↵
    2. Fekry B,
    3. Ugartemendia L,
    4. Esnaola NF,
    5. Goetzl L.
    Extracellular vesicles, circadian rhythms, and cancer: a comprehensive review with emphasis on hepatocellular carcinoma. Cancers. 2024; 16: 2552.
    OpenUrlPubMed
  98. 98.↵
    2. Pein M,
    3. Insua-Rodríguez J,
    4. Hongu T,
    5. Riedel A,
    6. Meier J,
    7. Wiedmann L, et al.
    Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat Commun. 2020; 11: 1494.
    OpenUrlCrossRefPubMed
  99. 99.↵
    2. Abbas T,
    3. Dutta A.
    p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009; 9: 400–14.
    OpenUrlCrossRefPubMed
  100. 100.↵
    2. Gery S,
    3. Komatsu N,
    4. Baldjyan L,
    5. Yu A,
    6. Koo D,
    7. Koeffler HP.
    The circadian gene Per1 plays an important role in cell growth and DNA damage control in human cancer cells. Mol Cell. 2006; 22: 375–82.
    OpenUrlCrossRefPubMed
  101. 101.↵
    2. Mir SE,
    3. De Witt Hamer PC,
    4. Krawczyk PM,
    5. Balaj L,
    6. Claes A,
    7. Niers JM, et al.
    In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. Cancer Cell. 2010; 18: 244–57.
    OpenUrlCrossRefPubMed
  102. 102.↵
    2. Farshadi E,
    3. Yan J,
    4. Leclere P,
    5. Goldbeter A,
    6. Chaves I,
    7. van der Horst GTJ.
    The positive circadian regulators CLOCK and BMAL1 control G2M/M cell cycle transition through Cyclin B1. Cell Cycle. 2019; 18: 16–33.
    OpenUrlCrossRefPubMed
  103. 103.↵
    2. Kondratov RV,
    3. Antoch MP.
    Circadian proteins in the regulation of cell cycle and genotoxic stress responses. Trends Cell Biol. 2007; 17: 311–7.
    OpenUrlCrossRefPubMed
  104. 104.↵
    2. Lee Y,
    3. Lahens NF,
    4. Zhang S,
    5. Bedont J,
    6. Field JM,
    7. Sehgal A.
    G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol. 2019; 17: e3000228.
  105. 105.↵
    2. Fu XJ,
    3. Li HX,
    4. Yang K,
    5. Chen D,
    6. Tang H.
    The important tumor suppressor role of PER1 in regulating the cyclin-CDK-CKI network in SCC15 human oral squamous cell carcinoma cells. Onco Targets Ther. 2016; 9: 2237–45.
    OpenUrlPubMed
  106. 106.↵
    2. Wang Q,
    3. Ao Y,
    4. Yang K,
    5. Tang H,
    6. Chen D.
    Circadian clock gene Per2 plays an important role in cell proliferation, apoptosis and cell cycle progression in human oral squamous cell carcinoma. Oncol Rep. 2016; 35: 3387–94.
    OpenUrlPubMed
  107. 107.↵
    2. Han Y,
    3. Meng F,
    4. Venter J,
    5. Wu N,
    6. Wan Y,
    7. Standeford H, et al.
    miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth. J Hepatol. 2016; 64: 1295–304.
    OpenUrlPubMed
  108. 108.↵
    2. Wang Y,
    3. Kojetin D,
    4. Burris TP.
    Anti-proliferative actions of a synthetic REV-ERBα/β agonist in breast cancer cells. Biochem Pharmacol. 2015; 96: 315–22.
    OpenUrlCrossRefPubMed
  109. 109.↵
    2. Goswami S,
    3. Walle T,
    4. Cornish AE,
    5. Basu S,
    6. Anandhan S,
    7. Fernandez I, et al.
    Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma. Nat Med. 2020; 26: 39–46.
    OpenUrlCrossRefPubMed
  110. 110.↵
    2. Pu H,
    3. Bailey LC,
    4. Bauer LG,
    5. Voronkov M,
    6. Baxter M,
    7. Huber KVM, et al.
    Pharmacological targeting of BMAL1 modulates circadian and immune pathways. Nat Chem Biol. 2025; 21: 736–45.
    OpenUrlCrossRefPubMed
  111. 111.↵
    2. Gul S,
    3. Akyel YK,
    4. Gul ZM,
    5. Isin S,
    6. Ozcan O,
    7. Korkmaz T, et al.
    Discovery of a small molecule that selectively destabilizes Cryptochrome 1 and enhances life span in p53 knockout mice. Nat Commun. 2022; 13: 6742.
    OpenUrlPubMed
  112. 112.
    2. Liu JL,
    3. Wang CY,
    4. Cheng TY,
    5. Rixiati Y,
    6. Ji C,
    7. Deng M, et al.
    Circadian clock disruption suppresses PDL1+ intraepithelial B cells in experimental colitis and colitis-associated colorectal cancer. Cell Mol Gastroenterol Hepatol. 2021; 12: 251–76.
    OpenUrlPubMed
  113. 113.
    2. Zhang W,
    3. He W,
    4. Shi Y,
    5. Zhao J,
    6. Liu S,
    7. Zhang F, et al.
    Aberrant TIMELESS expression is associated with poor clinical survival and lymph node metastasis in early-stage cervical carcinoma. Int J Oncol. 2017; 50: 173–84.
    OpenUrlPubMed
  114. 114.
    2. Huisman SA,
    3. Ahmadi AR,
    4. JN IJ,
    5. Verhoef C,
    6. van der Horst GT,
    7. de Bruin RW.
    Disruption of clock gene expression in human colorectal liver metastases. Tumour Biol. 2016; 37: 13973–81.
    OpenUrlPubMed
  115. 115.
    2. Wang X,
    3. Yan D,
    4. Teng M,
    5. Fan J,
    6. Zhou C,
    7. Li D, et al.
    Reduced expression of PER3 is associated with incidence and development of colon cancer. Ann Surg Oncol. 2012; 19: 3081–8.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Email Article
Citation Tools

Jump to section

Keywords