Introduction
Circadian regulation in cancer biology
The promise and challenges of cancer chronotherapy
The future of circadian medicine in cancer care
References
Further reading
Circadian rhythms influence cancer biology, treatment response, toxicity, and patient outcomes by affecting cellular processes, metabolism, immunity, sleep, and hormonal signaling. Aligning therapies with individual biological timing could improve cancer care, but clinical benefits vary by treatment, tumor type, sex, and circadian phase.
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Introduction
The circadian clock regulates a wide range of biological processes that maintain cellular homeostasis. Disruptions to these internal rhythms may contribute to cancer development and progression, which has driven researchers to explore new therapeutic strategies like chronotherapy that align cancer treatment with individual circadian biology. In mammals, a central clock in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates peripheral clocks distributed throughout tissues and organs through neural, hormonal, metabolic, and temperature-related signals.1,2,3
Circadian regulation in cancer biology
Circadian rhythms are endogenous, approximately 24-hour oscillations that regulate sleep-wake behavior and tissue-specific physiological and cellular processes.1,2,3 Circadian variations are evident in a wide range of essential physiological and biological processes, including DNA repair, cell cycle progression, hormone release, metabolism, and memory consolidation in the brain. At the molecular level, the core clock includes a transcription-translation feedback system in which CLOCK and BMAL1 promote expression of PERIOD (PER) and CRYPTOCHROME (CRY) proteins, which subsequently feed back to inhibit CLOCK-BMAL1 activity and generate rhythmic gene expression.1,2,3
Dysregulation of these pathways due to circadian disruptions can contribute to genomic instability, the proliferation of cancer cells, and altered immune function that enhance cancer survival and progression1. Specifically, dysregulation of brain and muscle ARNT-like protein 1 (BMAL1) and circadian locomotor output cycles Kaput (CLOCK) can influence c-Myc, Wnt/β-catenin, and Akt/mTOR pathways, all of which promote tumor growth, progression, and metastasis. However, the effects of individual clock components are context-dependent: depending on tumor type, genetic background, and disease stage, circadian proteins can exert either tumor-promoting or tumor-suppressive effects.1,2,3
BMAL1 also regulates the activity of the tumor suppressor p53 and its downstream signaling, which may alter p53-mediated responses to DNA damage and apoptosis when circadian regulation is disrupted.1 Upregulation of the unfolded protein response (UPR) by BMAL1 supports the survival of cancer cells and their ability to respond to stressful conditions by enhancing adaptive protein-folding mechanisms and the degradation of misfolded proteins.1
Circadian rhythms are regulated by intrinsic biological processes; however, they are also influenced by lifestyle, genetic, and external factors. For example, night shift workers and other individuals with chronic circadian dysfunction have shown epidemiological associations with increased incidence of several cancers, including breast, prostate, and colorectal cancers, although the strength of evidence varies by cancer type and exposure pattern.1,2,3 Exposure to light at night also suppresses melatonin production, which may diminish melatonin-mediated antiproliferative and other antitumor effects.2,3
Among people with cancer, disruption of sleep, rest-activity rhythms, and diurnal cortisol patterns has also been associated with fatigue, depression, impaired quality of life, disease progression, and, in some patient groups, shorter survival. Flattened diurnal cortisol slopes and disrupted actigraphy-derived rest-activity rhythms have therefore been investigated as potential markers of circadian dysfunction and prognosis, although these associations do not establish that circadian disruption itself causes poorer outcomes.4
How are circadian rhythm and circulating tumor cells related?
The promise and challenges of cancer chronotherapy
Chronotherapy is an emerging therapeutic strategy that leverages circadian rhythms to enhance drug efficacy while minimizing potential side effects. In oncology, the specified timing of cisplatin, 5-fluorouracil (5-FU), and doxorubicin has been shown to enhance their anti-cancer activity while reducing toxicity to non-cancerous tissues.1,2 Clinical benefits are not uniform across regimens or patient populations, however. A systematic review of 18 randomized controlled trials found reduced toxicity with chronomodulated chemotherapy in 61% of studies, whereas only 17% reported improved efficacy; some trials reported mixed or worse toxicity outcomes.4
Adjusting treatment schedules may also mitigate the severity of adverse effects such as gastrointestinal distress, myelosuppression, and cardiotoxicity, potentially supporting patient quality of life and treatment adherence1. In advanced melanoma, retrospective data have associated later immune checkpoint inhibitor (ICI) administration with poorer survival. In one propensity score-matched analysis summarized in the literature, patients receiving at least 20% of their ICI infusions after 4:30 PM had poorer overall survival than those receiving fewer late-day infusions. This observational association does not establish a universal 4:30 PM treatment cutoff or demonstrate that earlier infusion itself causes improved survival.1,2
Clinical evidence for cancer chronotherapy remains heterogeneous, and optimal timing can depend on treatment, tumor type, sex, and individual circadian phase. A meta-analysis of three phase III metastatic colorectal cancer trials, for example, reported a survival advantage from chronomodulated chemotherapy in men but not women.4 For example, the administration of doxorubicin in the morning (approximately 06:00 in studied schedules) and cisplatin in the evening (approximately 16:00–20:00) has been associated with fewer complications and side effects among patients diagnosed with ovarian, advanced/recurrent endometrial carcinoma, and metastatic bladder cancer.2
Anticancer therapy could take advantage of the mitotic rhythmicity of cells and apply the treatment depending on the time-of-day efficacy.2”
Cancer cell sensitivity to radiation may also vary throughout the day, with some circadian genes involved in DNA repair pathways that respond to ionizing radiation. Clinical findings are inconsistent: studies have reported time-of-day differences in survival, tumor response, or treatment toxicity in some cancers, whereas others, including studies of high-grade glioma, have found no survival difference between morning and afternoon treatment.2 Nevertheless, additional research is needed to clarify how chronoradiotherapy may improve patient outcomes and survival rates. Current evidence suggests that reducing treatment-related toxicity may be a more consistent goal of chronoradiotherapy than improving tumor control or overall survival.2
Although the results are promising, integrating chronotherapy into existing care practices has been challenging. Cancer care centers and hospitals typically work during daytime hours, thus limiting the feasibility of prescribing treatments late at night or very early in the morning.1 Additional limitations that further complicate the implementation of chronotherapy into cancer care include interindividual variations in sleep schedule preferences, diet, and physical activity. 1,2 Age, sex, chronotype, medication schedules, tumor composition and genetics, and differences between a patient's systemic circadian phase and the tumor's own rhythmicity may further alter the optimal treatment window.1,2,3 Tumors may themselves retain circadian oscillations and respond to systemic timing cues such as glucocorticoids, body temperature, and feeding-related metabolic signals, adding another layer of complexity to treatment scheduling.3
Circadian-supportive interventions may also complement treatment timing. Bright-light therapy has shown potential to reduce cancer-related fatigue and deterioration of circadian rhythms during treatment, while cognitive behavioral therapy for insomnia and physical activity can improve sleep-related outcomes in patients and survivors. Evidence that these interventions directly improve cancer survival, however, remains limited.4
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The future of circadian medicine in cancer care
The clinical application of chronotherapy across medical specialties is limited by several challenges that necessitate further mechanistic and clinical research. Elucidating how mediating factors such as age, sex, comorbidities, and tumor-specific characteristics influence patient responses to chronotherapy will be essential, as will better understanding the bidirectional relationship between circadian rhythms and anticancer drug activity. Reliable biomarkers of individual circadian phase, together with information about tumor clock function, will also be important if treatment is to be timed according to biological rather than simply clock time.1,2,3
Modern fitness trackers and smartwatches can provide longitudinal information on sleep-wake patterns and physical activity, while research-grade actigraphy and related wearable devices can additionally characterize rest-activity and light-exposure rhythms.1,3,4 Such information could eventually be combined with computational models or programmable drug-delivery systems to help individualize treatment schedules, but this approach remains under development rather than routine oncology practice.1,3
Wearable and biosensor technologies capable of tracking physiological signals relevant to circadian phase are also being investigated, including approaches that assess temperature and biochemical rhythms.1 As these data continue to emerge, it is crucial to integrate biological, clinical, and treatment-response information to develop predictive frameworks that can guide personalized chronotherapy strategies. Innovative approaches, particularly those that leverage artificial intelligence (AI), have the potential to accelerate this translation to predict patient responses and optimize therapeutic timing. However, AI- and machine-learning-guided cancer chronotherapy remains a research direction and requires prospective clinical validation before it can be considered an established method for treatment selection or scheduling.1
References
- El-Tanani, M., Rabbani, S. A., Ali, A. A. et al. (2024). Circadian rhythms and cancer: implications for timing in therapy. Discover Oncology, 15, 767. DOI: 10.1007/s12672-024-01643-4, https://link.springer.com/article/10.1007/s12672-024-01643-4
- Amiama-Roig, A., Verdugo-Sivianes, E. M., Carnero, A., & Blanco, J. R. (2022). Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy. Cancers 14(20). DOI: 10.3390/cancers14205071. https://www.mdpi.com/2072-6694/14/20/5071
- Damato, A. R., & Herzog, E. D. (2022). Circadian clock synchrony and chronotherapy opportunities in cancer treatment. Seminars in Cell & Developmental Biology 126; 27-36. DOI: 10.1016/j.semcdb.2021.07.017. https://www.sciencedirect.com/science/article/abs/pii/S1084952121002044?via%3Dihub
- Jagielo, A. D., Benedict, C., & Spiegel, D. (2023). Circadian, hormonal, and sleep rhythms: Effects on cancer progression implications for treatment. Frontiers in Oncology 13; 1269378. DOI: 10.3389/fonc.2023.1269378, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1269378/full
Further Reading
Last Updated: Aug 12, 2026
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