J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website https://jocmr.elmerjournals.com

Review

Volume 18, Number 7, July 2026, pages 437-448

Circadian Rhythms in Colorectal Cancer: Recent Advances in Development and Treatment

↓ Figure 1. Circadian disruption drives metabolic reprogramming in the CRC TME. Overview of the glycolysis/lactate accumulation pathway driven by BMAL1/PER2 loss, highlighting the suppression of CD8⁺ T cells and promotion of MDSCs. CRC: colorectal cancer; TME: tumor microenvironment; MDSCs: myeloid-derived suppressor cells. BMAL1: brain and muscle ARNT like 1; CRC: colorectal cancer; NADH: reduced nicotinamide adenine dinucleotide; ATP: adenosine triphosphate.

↓ Figure 2. Circadian regulation of the immune microenvironment and its impact on CRC. Schematic of circadian-regulated PD-L1⁺ MDSC abundance and CD8⁺ T cell infiltration, showing the temporal window for anti-PD-L1 therapy. PD-L1: programmed death ligand 1; anti-PD-L1: anti programmed death ligand 1 antibody; CRC: colorectal cancer; TAM: tumor-associated macrophage; MDSC: myeloid-derived suppressor cell; IL: interleukin; VEGF: vascular endothelial growth factor; Treg: regulatory T cell; CTL: cytotoxic T lymphocyte; NK: natural killer cell.

↓ Figure 3. Circadian control of the stromal-physical microenvironment in CRC. Illustration of NONO-mediated CAF reprogramming and the HIF-1α/BMAL1-driven VEGF oscillation affecting ECM remodeling. BMAL1: brain and muscle ARNT like 1; CAF: cancer associated fibroblast; CRC: colorectal cancer; HIF-1α: hypoxia inducible factor 1 alpha; NONO: non-POU domain-containing octamer-binding protein; VEGF: vascular endothelial growth factor; EMT: epithelial–mesenchymal transition; ECM: extracellular matrix; TGF-β: transforming growth factor beta.

↓ **Table 1.** Circadian Regulation of the Tumor Microenvironment in Colorectal Cancer
TME compartment	Key molecules/pathways	Cells involved	Role	Mechanism	References
PD-L1: programmed death ligand 1; BMAL1: brain and muscle ARNT like 1; CAF: cancer associated fibroblast; HIF-1α: hypoxia inducible factor 1 alpha; integrin beta 1; NONO: non-POU domain-containing octamer-binding protein; PAI-1: plasminogen activator inhibitor 1; SCFA: short-chain fatty acid; SDC1: syndecan-1; TAM: tumor-associated macrophage; TGF-β: transforming growth factor beta; TME: tumor microenvironment; Treg: regulatory T cell; VEGF: vascular endothelial growth factor; EMT: epithelial–mesenchymal transition; IL: interleukin.
Metabolic microenvironment	MYC/HIF-1α	Tumor cells	Promotes glycolysis, lactate production	Loss of clock genes (BMAL1/PER2/CRY2) activates this signaling axis.	[24, 27, 28]
	Lactate	CD8⁺ T, MDSC, TAM	Suppresses CD8⁺ T-cell activity; promotes MDSC/TAM immunosuppressive phenotypes	Lactate serves as a signaling molecule that directly modulates immune cell function.	[29, 30]
	Taurocholic acid (TCA)	MDSC	Enhances MDSC glycolysis; stabilizes PD-L1 expression	Circadian disruption → microbial metabolite accumulation → epigenetic glycolysis enhancement + PD-L1 ubiquitination inhibition	[31]
Immune microenvironment	PD-L1⁺ MDSC	MDSC	Forms immunosuppressive niche	Circadian disruption → altered epithelial clock → local cytokine changes → increased MDSC and neutrophil recruitment	[32]
	CD8⁺ T cells	CD8⁺ T cells	Antitumor immune exhaustion	Circadian disruption reduces infiltration and cytotoxicity; endothelial cells mediate oscillation	[33]
	Macrophages (M1/M2)	Macrophages	Phagocytosis, secretion, polarization fluctuate daily	Subject to phase-dependent circadian regulation.	[35, 36]
	SCFAs, BAs	CD8⁺ T, Treg, TAM, MDSC	Regulate immune cell function; affect vascular remodeling	Circadian disruption → altered gut microbiota metabolites → immune cell remodeling	[37]
	TGF-β, IL-6	CAFs, endothelial cells	Activate CAFs and promote myofibroblast phenotype; stimulate angiogenesis	Immune cells release TGF-β/IL-6 → CAF activation + angiogenesis, linking immune and stromal compartments	[26, 40]
Stromal microenvironment	NONO, ITGB1, SDC1, CD47	Tumor cells, CAFs	Enhance tumor cell receptivity to CAF-derived signals, promoting invasion and metastasis	NONO upregulates receptor expression, sensitizing tumor cells to TENASCIN/THBS pathways	[41]
	VEGF, HIF-1α, BMAL1, hClock	Endothelial cells, tumor cells	Promote angiogenesis, induce EMT, facilitate metastasis	HIF-1α and BMAL1 cooperatively drive rhythmic VEGF expression; hClock activates this axis	[42, 43]
	PAI-1, TGF-β, collagen	CAFs, tumor cells	Regulate ECM fibrosis and stiffness, promote invasion	Bmal1 loss → PAI-1↓ → fibrinolysis↑ → TGF-β activation → myCAF phenotype + fibrosis	[44]
	HIF-1α, BMAL1	Tumor cells, stromal cells	Form a hypoxia-positive feedback loop, sustaining pro-tumor microenvironment	HIF-1α and BMAL1 share overlapping genomic targets; hypoxic signaling in turn dampens circadian rhythmicity, thereby establishing a positive feedback loop	[46]

↓ Table 1. Circadian Regulation of the Tumor Microenvironment in Colorectal Cancer

TME compartment

Key molecules/pathways

Cells involved

Role

Mechanism

References

PD-L1: programmed death ligand 1; BMAL1: brain and muscle ARNT like 1; CAF: cancer associated fibroblast; HIF-1α: hypoxia inducible factor 1 alpha; integrin beta 1; NONO: non-POU domain-containing octamer-binding protein; PAI-1: plasminogen activator inhibitor 1; SCFA: short-chain fatty acid; SDC1: syndecan-1; TAM: tumor-associated macrophage; TGF-β: transforming growth factor beta; TME: tumor microenvironment; Treg: regulatory T cell; VEGF: vascular endothelial growth factor; EMT: epithelial–mesenchymal transition; IL: interleukin.

Metabolic microenvironment

MYC/HIF-1α

Tumor cells

Promotes glycolysis, lactate production

Loss of clock genes (BMAL1/PER2/CRY2) activates this signaling axis.

[24, 27, 28]

Lactate

CD8⁺ T, MDSC, TAM

Suppresses CD8⁺ T-cell activity; promotes MDSC/TAM immunosuppressive phenotypes

Lactate serves as a signaling molecule that directly modulates immune cell function.

[29, 30]

Taurocholic acid (TCA)

MDSC

Enhances MDSC glycolysis; stabilizes PD-L1 expression

Circadian disruption → microbial metabolite accumulation → epigenetic glycolysis enhancement + PD-L1 ubiquitination inhibition

[31]

Immune microenvironment

PD-L1⁺ MDSC

MDSC

Forms immunosuppressive niche

Circadian disruption → altered epithelial clock → local cytokine changes → increased MDSC and neutrophil recruitment

[32]

CD8⁺ T cells

Antitumor immune exhaustion

Circadian disruption reduces infiltration and cytotoxicity; endothelial cells mediate oscillation

[33]

Macrophages (M1/M2)

Macrophages

Phagocytosis, secretion, polarization fluctuate daily

Subject to phase-dependent circadian regulation.

[35, 36]

SCFAs, BAs

CD8⁺ T, Treg, TAM, MDSC

Regulate immune cell function; affect vascular remodeling

Circadian disruption → altered gut microbiota metabolites → immune cell remodeling

[37]

TGF-β, IL-6

CAFs, endothelial cells

Activate CAFs and promote myofibroblast phenotype; stimulate angiogenesis

Immune cells release TGF-β/IL-6 → CAF activation + angiogenesis, linking immune and stromal compartments

[26, 40]

Stromal microenvironment

NONO, ITGB1, SDC1, CD47

Tumor cells, CAFs

Enhance tumor cell receptivity to CAF-derived signals, promoting invasion and metastasis

NONO upregulates receptor expression, sensitizing tumor cells to TENASCIN/THBS pathways

[41]

VEGF, HIF-1α, BMAL1, hClock

Endothelial cells, tumor cells

Promote angiogenesis, induce EMT, facilitate metastasis

HIF-1α and BMAL1 cooperatively drive rhythmic VEGF expression; hClock activates this axis

[42, 43]

PAI-1, TGF-β, collagen

CAFs, tumor cells

Regulate ECM fibrosis and stiffness, promote invasion

Bmal1 loss → PAI-1↓ → fibrinolysis↑ → TGF-β activation → myCAF phenotype + fibrosis

[44]

HIF-1α, BMAL1

Tumor cells, stromal cells

Form a hypoxia-positive feedback loop, sustaining pro-tumor microenvironment

HIF-1α and BMAL1 share overlapping genomic targets; hypoxic signaling in turn dampens circadian rhythmicity, thereby establishing a positive feedback loop

[46]

↓ **Table 2.** Clinical Evidence of Chronotherapeutic and Circadian-Based Interventions in Colorectal Cancer
Cancer type/stage	Intervention	Intervention group (summary)	Control group (summary)	Key significant differences (intervention vs control)	References
RR: risk ratio; CI: confidence interval; HR: hazard ratio; CBT: cognitive behavioral therapy; chronoFLO4: chronomodulated floxuridine-based 4-day regimen; CRC: colorectal cancer; FOLFOX: folinic acid + fluorouracil + oxaliplatin; LARC: locally advanced rectal cancer; mCRC: metastatic colorectal cancer; PFS: progression-free survival; TRE: time-restricted eating.
mCRC, stage IV	Chronomodulated chemotherapy	Chemotherapy infusion timed to circadian peaks (e.g., oxaliplatin, 5-FU)	Conventional constant-rate infusion (without chronomodulation)	Significantly reduced hematological toxicity (RR = 0.36; 95% CI, 0.27–0.48); objective response rate increased from 29% to 51% (P = 0.003)	[68]
	Chronomodulated FOLFOX	ChronoFLO4 regimen (4-day chronomodulated infusion)	FOLFOX2 regimen (2-day conventional infusion)	Significant benefit in males (HR = 0.75, P = 0.02), opposite effect in females (HR = 1.38, P = 0.03); overall survival comparable	[69]
	Chronomodulated chemotherapy + oxaliplatin	Chronomodulated 5-FU + leucovorin + oxaliplatin	Chronomodulated 5-FU + leucovorin (without oxaliplatin)	Objective response rate increased from 16% to 53% (P < 0.001); median PFS extended from 6.1 to 8.7 months (P = 0.048)	[70]
	Chronomodulated Chemotherapy + Irinotecan	Chronomodulated irinotecan infusion (peak at one of six different circadian time points) + fixed-schedule chronomodulated FOLFOX	Same regimen at different circadian time points	Significant sex differences (P < 0.05): morning administration recommended for males, afternoon for females	[46]
	Chronomodulated chemoradiotherapy	Chronomodulated concurrent chemoradiotherapy (radiation and chemotherapy timed according to circadian rhythms)	Conventional-timing chemoradiotherapy	Trends toward improvement in certain parameters; requires validation in larger studies	[23]
	Melatonin adjuvant therapy	Melatonin supplementation (standard dose, evening administration)	Placebo or no supplementation	23–41% reduction in CRC risk among shift workers; 53% reduction in radiotherapy-associated oral mucositis	[71]
Locally advanced rectal cancer (LARC, stages II–III)	Circadian rhythm and dietary intervention	Stable circadian rhythm + high dietary polyphenol intake	Standard care	Circadian rhythm stability and high dietary polyphenol intake associated with improved neoadjuvant therapy response	[72]
	Perioperative multicomponent behavioral intervention	Multicomponent behavioral program targeting circadian rhythm and gut–brain axis	Standard care	Associated with improvements in neuroimmune features and symptom outcomes	[73]
	Chronomodulated chemoradiotherapy	Chronomodulated chemoradiotherapy regimen (radiation timed according to circadian rhythm)	Conventional chemoradiotherapy	Faster recovery of peripheral blood white blood cell counts; fewer treatment delays; trend toward improved local control	[74]
Postoperative/adjuvant therapy and survivors (stages I–III)	Integrated sleep and psychological intervention	Sleep hygiene education + relaxation training + stimulus control + CBT	Standard oncological care	Significantly improved postoperative recovery and quality of life	[75]
	Behavioral activation	Behavioral activation intervention targeting sleep disorders	Standard care	Significantly improved sleep disturbances, quality of life, and psychological distress (P < 0.05)	[66]
	Circadian eating pattern intervention	Adjusted eating time windows and meal frequency	Conventional eating pattern	Longer energy intake window associated with less fatigue (P < 0.05)	[76]
High-risk populations (obesity/early-onset CRC)	TRE	8-h TRE (12:00 pm–8:00 pm)	Daily 25% calorie restriction or control group	Ongoing trial: assessing weight loss, metabolic improvement, and CRC risk reduction	[23]
	TRE + mindfulness intervention	8-week remote TRE (12:00 pm–8:00 pm) + mindfulness sessions	Standard care	Good feasibility and acceptability, providing basis for larger-scale trials	[4]

↓ Table 2. Clinical Evidence of Chronotherapeutic and Circadian-Based Interventions in Colorectal Cancer

Cancer type/stage

Intervention

Intervention group (summary)

Control group (summary)

Key significant differences (intervention vs control)

References

RR: risk ratio; CI: confidence interval; HR: hazard ratio; CBT: cognitive behavioral therapy; chronoFLO4: chronomodulated floxuridine-based 4-day regimen; CRC: colorectal cancer; FOLFOX: folinic acid + fluorouracil + oxaliplatin; LARC: locally advanced rectal cancer; mCRC: metastatic colorectal cancer; PFS: progression-free survival; TRE: time-restricted eating.

mCRC, stage IV

Chronomodulated chemotherapy

Chemotherapy infusion timed to circadian peaks (e.g., oxaliplatin, 5-FU)

Conventional constant-rate infusion (without chronomodulation)

Significantly reduced hematological toxicity (RR = 0.36; 95% CI, 0.27–0.48); objective response rate increased from 29% to 51% (P = 0.003)

[68]

Chronomodulated FOLFOX

ChronoFLO4 regimen (4-day chronomodulated infusion)

FOLFOX2 regimen (2-day conventional infusion)

Significant benefit in males (HR = 0.75, P = 0.02), opposite effect in females (HR = 1.38, P = 0.03); overall survival comparable

[69]

Chronomodulated chemotherapy + oxaliplatin

Chronomodulated 5-FU + leucovorin + oxaliplatin

Chronomodulated 5-FU + leucovorin (without oxaliplatin)

Objective response rate increased from 16% to 53% (P < 0.001); median PFS extended from 6.1 to 8.7 months (P = 0.048)

[70]

Chronomodulated Chemotherapy + Irinotecan

Chronomodulated irinotecan infusion (peak at one of six different circadian time points) + fixed-schedule chronomodulated FOLFOX

Same regimen at different circadian time points

Significant sex differences (P < 0.05): morning administration recommended for males, afternoon for females

[46]

Chronomodulated chemoradiotherapy

Chronomodulated concurrent chemoradiotherapy (radiation and chemotherapy timed according to circadian rhythms)

Conventional-timing chemoradiotherapy

Trends toward improvement in certain parameters; requires validation in larger studies

[23]

Melatonin adjuvant therapy

Melatonin supplementation (standard dose, evening administration)

Placebo or no supplementation

23–41% reduction in CRC risk among shift workers; 53% reduction in radiotherapy-associated oral mucositis

[71]

Locally advanced rectal cancer (LARC, stages II–III)

Circadian rhythm and dietary intervention

Stable circadian rhythm + high dietary polyphenol intake

Standard care

Circadian rhythm stability and high dietary polyphenol intake associated with improved neoadjuvant therapy response

[72]

Perioperative multicomponent behavioral intervention

Multicomponent behavioral program targeting circadian rhythm and gut–brain axis

Standard care

Associated with improvements in neuroimmune features and symptom outcomes

[73]

Chronomodulated chemoradiotherapy

Chronomodulated chemoradiotherapy regimen (radiation timed according to circadian rhythm)

Conventional chemoradiotherapy

Faster recovery of peripheral blood white blood cell counts; fewer treatment delays; trend toward improved local control

[74]

Postoperative/adjuvant therapy and survivors (stages I–III)

Integrated sleep and psychological intervention

Sleep hygiene education + relaxation training + stimulus control + CBT

Standard oncological care

Significantly improved postoperative recovery and quality of life

[75]

Behavioral activation

Behavioral activation intervention targeting sleep disorders

Standard care

Significantly improved sleep disturbances, quality of life, and psychological distress (P < 0.05)

[66]

Circadian eating pattern intervention

Adjusted eating time windows and meal frequency

Conventional eating pattern

Longer energy intake window associated with less fatigue (P < 0.05)

[76]

High-risk populations (obesity/early-onset CRC)

TRE

8-h TRE (12:00 pm–8:00 pm)

Daily 25% calorie restriction or control group

Ongoing trial: assessing weight loss, metabolic improvement, and CRC risk reduction

[23]

TRE + mindfulness intervention

8-week remote TRE (12:00 pm–8:00 pm) + mindfulness sessions

Standard care

Good feasibility and acceptability, providing basis for larger-scale trials

[4]