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Review
. 2024 Apr 27;10(1):199.
doi: 10.1038/s41420-024-01960-1.

Circadian rhythm regulates the function of immune cells and participates in the development of tumors

Yuen Zeng #  1 , Zichan Guo #  2 , Mengqi Wu  1 , Fulin Chen  2 , Lihua Chen  3
Affiliations
Review

Circadian rhythm regulates the function of immune cells and participates in the development of tumors

Yuen Zeng et al. Cell Death Discov. .

Abstract

Circadian rhythms are present in almost all cells and play a crucial role in regulating various biological processes. Maintaining a stable circadian rhythm is essential for overall health. Disruption of this rhythm can alter the expression of clock genes and cancer-related genes, and affect many metabolic pathways and factors, thereby affecting the function of the immune system and contributing to the occurrence and progression of tumors. This paper aims to elucidate the regulatory effects of BMAL1, clock and other clock genes on immune cells, and reveal the molecular mechanism of circadian rhythm's involvement in tumor and its microenvironment regulation. A deeper understanding of circadian rhythms has the potential to provide new strategies for the treatment of cancer and other immune-related diseases.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Circadian rhythm mechanism.
The master clock affecting the body’s circadian rhythm is located in the hypothalamic suprachiasmatic nucleus (SCN), and the synchronization signal is transmitted from the SCN clock to the peripheral clock. The heterodimer complex CLOCK/BMAL1 acts on E-box elements on target genes. After synthesis, PER and CRY accumulate in the cytoplasm and form heterodimers that shuttle between the nucleus and cytoplasm. After phosphorylation under the action of CK1δ and CK1ε, they inhibit the transcription of E-box genes by blocking CLOCK/BMAL1-mediated transcription; REV-ERBα inhibits the expression of Bmal1 by binding to the ROR responsive element (RRE) in the promoter, while RORα has the opposite activation effect.
Fig. 2
Fig. 2. The effect of circadian rhythm on immune cells.
Circadian rhythm can influence immune cell function and response by modulating specific genes and signaling pathways, thereby affecting the balance and functionality of the entire immune system. In macrophages, circadian rhythm can affect Toll-like receptor activation and downstream signaling pathways, regulating immune activity and inflammatory response. Additionally, circadian rhythm can impact macrophage polarization, metabolic pathway selection, and other factors, thus affecting their ability to participate in inflammation and immune function. For dendritic cells, circadian rhythm can affect their maturation, antigen presentation, and migration functions. As for B cells, their development and migration can be influenced by circadian rhythm, but the underlying mechanisms require further research. In T cells, circadian rhythm can affect their migration, proliferation, and differentiation, thereby impacting their immune function and anti-tumor response. In Th17 cells, circadian rhythm can influence the expression of key genes such as NFIL3 and RORγt, affecting Th17 differentiation and function. Finally, circadian rhythm can also affect the number and function of NK cells, thus influencing their ability to clear tumor cells.
Fig. 3
Fig. 3. The sleep-wake cycle is involved in affecting immune system function and DNA damage repair.
Nighttime sleep, particularly in the early stages characterized by slow-wave sleep (SWS), promotes a shift towards Th1-mediated immune defense by inhibiting glucocorticoid release and promoting the release of growth hormone (GH) and prolactin. Sleep also inhibits Th2 cell production, further reinforcing Th1 dominance. Circadian rhythms regulate the secretion of cytokines and gut microbiota, significantly impacting the body’s inflammatory state. Sleep deprivation leads to abnormal cytokine secretion, altering the inflammatory state. Experimental sleep deprivation studies have shown increased immune response and elevated levels of inflammatory markers such as IL-6, TNF-α, and C-reactive protein in circulation. Monocytes are considered a primary factor in peripheral blood inflammation. Additionally, sleep deprivation affects the expression of inflammatory cytokines, circadian clock gene PER1, signaling molecules, and growth factor-related genes. Sleep is crucial for maintaining normal immune function, particularly enhancing cell-mediated immune responses. Furthermore, sleep deprivation disrupts circadian rhythms, impairs DNA damage repair, and increases the risk of cancer occurrence. Night shift workers often experience disrupted circadian rhythms, which interfere with cellular processes involved in DNA repair, cell cycle regulation, and inflammation, thereby increasing cancer risk. Studies have shown that sleep deprivation impairs the effective repair of DNA damage from both endogenous and exogenous sources. Moreover, disruptions in the expression of key genes involved in cell cycle checkpoints and DNA repair further indicate a direct link between circadian rhythm disturbances and the carcinogenic risk associated with night shift work. Severe sleep deprivation may exacerbate these effects, potentially leading to premature death in model organisms. Insufficient sleep not only affects brain function but also disrupts the body’s antioxidant response, leading to increased oxidative stress and DNA damage.
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