The circadian clock regulates sleep, and the central clock of the brain serves as a pacemaker for other molecular clocks in the peripheral organs, synchronizing sleep with external cues like light and food availability. The sleep wake cycle is determined by the inherent biological clock or circadian rhythm. The sleep phase occurs in a repetitive pattern or cycle of non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM), with each cycle lasting approximately 90 minutes (16). The physical illness, pain, treatment, and psychological effects of cancer may disrupt the sleep patterns of cancer patients (17). Disruption of individual sleep patterns can disrupt circadian rhythms, impair sleep cycles, and ultimately lead to a variety of human diseases, including sleep disorders, mental and neurodegeneration disorders, cardiovascular disease, and cancer (18–20).The relationship between circadian rhythm, sleep patterns, and exhaustion in patients with cancer, however, is still unclear.

The diagnosis and treatment of cancer seem to be associated with high levels of insomnia symptoms. One such example is the population with ovarian cancer, where the most common risk factor for sleep disorders is severe pain upon diagnosis. Tumor physiology itself may also play an important role here, such as the tumor or tumor microenvironment’s secretion of cytokines affecting metabolism and energy balance during sleep. According to a large longitudinal population survey, 31% of patients experience symptoms of insomnia in the perioperative period, and nearly 30% of patients match the diagnostic criteria for insomnia syndrome. In that study, 2 months later, the insomnia symptoms were relieved, and the remission rate was 32% (21).In another study, cancer survivors were found to be more likely to report sleep disorders after 2 years (22). A recent longitudinal study of American women’s health pointed out that among middle-aged women diagnosed with breast cancer, there was no difference in sleep problems before and after diagnosis (23).

Sleep problems often arise after surgical intervention. Poor postoperative sleep quality was present in over 70% of patients with cancer compared to baseline, and this condition tended to continue post-therapy (24). Body image disorder after treatment may be a significant predictor of poor sleep quality in patients receiving radical surgery. Beesley et al. noted that sleep duration but not sleep quality of patients with cancer improved 6 months after surgery (25). According to that study, more optimistic people typically felt less depressed and had better sleep. While neoadjuvant and adjuvant chemotherapy are frequently used along with surgery, which is the primary treatment for many malignancies, these treatments can also interfere with sleep. In women with cancer receiving palliative chemotherapy, one of the most common adverse effects was sleep disturbance, accounting for 24% of the outcome measures recorded, according to King et al. (26). Palesh found that 79.6% of patients in cycle 1 had insomnia symptoms during the chemotherapy phase in patients with different types of cancer, with a slight decrease in symptoms of insomnia by cycle 2 (10). Some patients experience good sleep in the first cycle of chemotherapy and exhibit insomnia symptoms in the second cycle. Sleep disturbances may arise in as many as 65% of patients undergoing adjuvant chemotherapy and radiation therapy (27). Research has found that up to 60% of prostate cancer patients receiving androgen deprivation therapy combined with radiotherapy experience sleep disorders (28). Additionally, the percentage of patients with cancer who fulfill the diagnostic criteria for insomnia is three times greater than that of the general population (10). Most cancer survivors getting combination therapy had sleep disturbances. Receiving therapy can be a difficult procedure, and medication-induced side effects are the most common cause of treatment-related sleep disorders. Patients treated for cancer often experience stress, pain, anxiety, depression, and higher levels of physical fatigue. One of most common causes of sleep delays or interruptions is pain because it can persistently disrupt sleep throughout the night (29), particularly in patients suffering from chemotherapy-induced peripheral neurotoxicity. In turn, sleep disruption further leads to hyperalgesia (30), forming a vicious cycle of mutual influence between the two. Fear of a cancer diagnosis, uncertainty about the therapy outcome, and fear of recurrence and death are the main causes of anxiety and depression. These may affect sleep through intrusive or focused thinking. Depression levels and cancer duration are important predictors of sleep quality. Cancer-related physical fatigue is often persistent during treatment and manifests as reduced motivation to perform daily chores such as laundry, work, and cooking (31). This physical fatigue is not diminished by sleep or rest. Sleep disorders in patients with cancer may be more severe in patients with cancer-related fatigue. Treatment-induced nausea, vomiting, urodynamic changes, hot flashes and respiratory problems often lead to sleep disruption (32). Women are more likely to experience nocturia and hot flashes, potentially interfering with their ability to fall back asleep. A deterioration in sleep quality during diagnosis, treatment, and after treatment may be due to shorter sleep duration overall and more awakenings.

Breast cancer has been linked to the highest incidence of sleeplessness when compared to other cancers, such as those of the prostate, gynecological, head and neck, urinary, or gastrointestinal. It characterizes low sleep efficiency, frequent wakefulness at night, long wakefulness after sleep, and daytime sleepiness. Besides the physical discomfort, pain, and hot flashes caused by breast cancer itself, the patient is highly uncertain about the treatment outcome. Concerns about body shape and hormonal changes caused by hormonal therapy can lead to sleep disorders in patients. Koopman et al. discovered that 63% of women with metastatic breast cancer had sleep difficulties (33), indicating that in advanced cancer, patients are more prone to experience these problems. Further risk factors for sleep disorders are women, young age, less education, less physical activity, vasoconstriction (particularly night sweats), reproduction, less social support, higher levels of social stress, life events, and external factors like light, noise, or interference from hospital staff during hospital stays or sleep-inducing nursing interventions (10).

Recent research reports suggest that individuals with sleep difficulties or diagnosed with sleep disorders at any point in their lives are more likely to be diagnosed with cancer (35), and sleep disorders can be explained as early symptoms and indications of tumor diseases, predicting short-term health outcomes (36). Studies have found that sleep disturbances may increase the risk of gastric, colorectal, and breast cancers, and the risk of cancer increases with the duration and severity of sleep disorders. In the prospective AGES-Reykjavik cohort study, it was found that men with sleep disturbances had a considerably higher risk of prostate cancer than those without sleep disruption (37). Research has found that both insufficient sleep and prolonged sleep can increase the risk of cancer, with people who sleep longer having a 22% higher risk of cancer compared to those who sleep for a normal number of hours (7 to 8 hours). Similar findings were obtained in patients with colorectal cancer(CRC). The study found that abnormal sleep patterns, including nocturnal timing, may also be linked to skin, colorectal, and ovarian cancer. Overall, nocturnal patterns, symptoms of insomnia, and excessive and insufficient sleep were highly predictive of an elevated risk of cancer. Lack of sleep can lower the body’s immune function and increase the risk of cancer. Long-term sleep has been associated with an elevated risk of cancer, with prior research indicating that it can negatively impact metabolite levels, neurocognitive function, and cardiovascular health (38). However, additional research is required to identify the potential pathophysiological pathways involved in extended sleep duration and increased cancer risk. Patients with a nocturnal pattern are at a higher risk for cancer, possibly with an additional burden of nocturnal pattern-induced circadian delay worsening the loss of circadian autonomic regulation of tumor cells, causing dyssynchrony in the circadian control of cellular metabolism (39). The study discovered that the sleep disorder and cancer risk-association may be mediated by the combined effects of age, occupation, and sleep disorders.

Another prevalent sleep issue among patients with cancer is OSAS. OSAS is a very common sleep breathing disorder, but it is severely underestimated in clinical practice. The pathophysiological processes related to OSAS, such as fragmented sleep and intermittent hypoxia, may affect normal neuroendocrine regulation and impair the body’s immune function (40). The associations of cancer at different anatomic sites and/or different pathologies with OSAS may differ. Studies have indicated an association between OSAS and elevated cancer incidence and mortality (41, 42), especially head and neck cancer (43), and its severity is an independent risk factor for cancer. In addition, peripheral inflammation may also be involved in the carcinogenic mechanism of OSAS. However, some studies have not discovered a strong correlation between OSAS and cancer (44, 45).

Sleep disturbances can encourage cancer cells to proliferate and migrate. It is likely that sleep disorders-induced circadian rhythm disturbances, decreased melatonin secretion, and inflammatory responses result in unregulated cell proliferation. Circadian disruptions can influence the expression of genes linked to tumor development and metastasis, DNA repair, cell cycle regulation, and apoptosis (46). Circadian dysregulation may also attenuate the efficacy of anti-cancer therapy (47). The World Health Organization currently lists circadian rhythm abnormalities as potential cancer-causing agents. Melatonin is the first nocturnal anti-cancer signal discovered in humans (48), which is affected by circadian disturbances and ambient light. Chen et al. showed melatonin to have a positive anti-cancer impact by preventing the formation of lung cancer in a Lewis animal model (49). One cross-sectional investigation confirmed the findings and discovered considerably lower melatonin levels in malignant non-small-cell lung carcinoma than in healthy volunteers. According to animal studies, the number of cytotoxic cells and the capacity of the immune system to react to tumor growth are significantly impacted by lack of sleep. Lack of sleep also promotes proinflammatory cytokine and induces an inflammatory microenvironment (50), and persistent inflammation leads to genetic instability, causing cell mutations. These may promote cancer onset and progression. Sleep deprivation can also raise peripheral blood gamma-aminobutyric acid (GABA) levels and promote the expression of miR-223-3p. Extracellular miR-223-3p promotes the polarization of M2-like macrophages by activating the macrophage mitogen-activated protein kinase pathway, increasing interleukin-17 (IL-17) secretion, and promoting tumor proliferation and migration (51).

Several studies have reported a 3.4-to 4.8-fold increase in mortality in patients with cancer having OSAS (41, 42). It is most likely because of the reconfiguration of the cytoskeleton and connexin brought on by intermittent hypoxia that endothelial barrier failure increases tumor cell escape and metastasis. Moreover, hypoxia causes angiogenesis and vascular development by enhancing the expression of angiogenic growth factors released by tumor cells and endothelial cells (52). In lung cancer patients, OSAS promotes the activation and enrichment of cancer associated fibroblasts (CAFs), hypoxia activates TGF β signaling in lung cancer cells and fibroblasts, and promotes epithelial mesenchymal transition (53). Recent studies have found that intermittent hypoxic environments stimulate cell proliferation and migration, which may be associated with increased miRNA expression and HIF-1 (54).

Epidemiological statistics indicate a correlation between anxiety and depression and a higher likelihood of sleep problems. Conversely, those who already have sleep disorders typically exhibit greater symptoms of anxiety and despair; There may be a vicious circle between the two. A substantial amount of evidence indicate that sleep disorders are independent risk factors for depression in healthy individuals and older individuals (55), as well as powerful predictors of depression and relapse in those with a history of depression (55, 56). On the other hand, survivors with better sleep had higher levels of happiness and fewer episodes of anxiety or sadness. A correlation between sleep disturbances and an inflammatory reaction to depression has been shown (56).

A direct link between sleep disorders and memory problems in humans and animals has been often shown (57). Sleep disorders in humans can impair motor programming, implicit memory, and working memory. There exists a strong correlation between sleep disorders and cognitive decline, as well as an elevated risk of postoperative delirium. This may be related to insufficient sleep, leading to neuronal damage and accumulation of waste products in the brain (58).

Research has found that sleep problems in cancer patients are associated with lower clinical prognosis and quality of life (59). Adequate sleep can increase the pain tolerance of cancer patients, while poor sleep may lead to increased postoperative pain, delayed healing, prolonged postoperative recovery and hospital stay, suboptimal treatment outcomes and interruptions, and decreased ability to perform daily tasks. These lead to a decline in quality of life (10, 15). Epidemiological studies report that untreated insomnia leads to associated increase in absenteeism, decreased workplace productivity, and work-related as well as motor vehicle accidents. Sleep disorders remain an independent predictor of cancer mortality, even after adjusting for variables including age, cortisol levels, estrogen receptor expression, and comorbid depression (3). According to Ren Shave, for every 10% increase in sleep efficiency, there is a 32% decrease in mortality. Studies found that both short (≤6 hours/day) and long (≥8 hours/day) sleep durations increase the risk of mortality compared with sleep of 7 hours/day (60, 61). This has also been confirmed in several recent large-scale studies (62, 63). New research suggests that sleep regularity can predict mortality more strongly than sleep duration. The higher the sleep regularity, the lower the risk of all-cause mortality by 20-48% and cancer mortality by 16-39% (64). This may be related to irregular sleep as a more direct measure of circadian rhythm disorder.

Excessive daytime sleepiness and sleep disturbance impact fatigue and its perception. Sleep disorders are thought to be a cause of cancer-related fatigue and often accompany cancer-related fatigue (65). Furthermore, circadian dysregulation increases the risk of obesity and associated metabolic disorders, such as diabetes, hypertension, inflammation, and cardiovascular disease (66). These increase the risk of cancer and adversely impact societal health and the economy.

Pharmacological methods are among the most popular choices for treating sleep disturbances in cancer survivors, particularly in their acute stage. This is like the general population with sleep disorders. Common pharmacologic therapies include symptomatic medications (such as pain, diarrhea, and cough relief) and the use of benzodiazepine-based and non-benzodiazepine hypnotics, as proposed by Pillai et al. (67). After benzodiazepine receptor agonist treatment, 47.7% of the participants were actively treated for remission. However, such drugs are often restricted to short-term use because of their residual effects, tolerability, dependence, withdrawal, and potential risks of abuse, as well as changes in sleep architecture. Common medications include antidepressants, antihistamines, zolpidem, melatonin (68), and dexmedetomidine. Antihistamines have been found to lower the quality of sleep, but they also cause narcolepsy. Zolpidem can reduce postoperative pain and fatigue, improve patients’ quality of life, and reduce the consumption of anesthetic drugs. Dexmedetomidine has the unique advantage of simulating a natural sleep state, making it easier for patients to wake up, minimizing respiratory impact, improving their cognitive function, and reducing the incidence of postoperative delirium (68). Mechanistically speaking, on the one hand, dexmedetomidine can weaken neuronal apoptosis and have a protective effect on neuronal damage. However, it can also lower norepinephrine (NE) release, greatly decreasing the interstitial space’s extracellular volume and speeding up the brain’s waste-removal process (69). Dexmedetomidine is commonly used in Patient Controlled Sleep (PCSL). PCSL, a technology that allows patients with chronic intractable insomnia to intermittently trigger measurable doses of dexmedetomidine through a patient-controlled device to produce and maintain natural sleep (70). However, its application is challenged considering its long treatment time (possibly up to 6 months), inconvenient patient mobility, increased risk of infection, uncertainty in the efficacy of dexmedetomidine alone, and potential side effects of long-term use. Ozone is a strong oxidizing agent, which was first used to prevent wound infections in soldiers during World War I (71). Studies discovered that three months of low-dose ozone therapy decreased anxiety, sadness, and sleep quality metrics and significantly raised serum levels of BDNF and GABA in individuals with insomnia (72).A recent study have found that propofol may be a potential treatment for chronic sleep disorders, which may be associated with REM sleep recovery, enhanced mPFC functional connectivity, and improved brain metabolism (73). Over time, clinical doctors have realized the necessity of multimodal sleep by adopting personalized treatment methods that integrate different drugs delivered by patient-controlled fusion pumps, improve sleep/wake cycles, treat complications caused by chronic insomnia, and provide vital signs and sleep monitoring. Among the medications utilized are lidocaine, scopolamine, sodium 4-hydroxybutyrate, propofol, ketamine, and dexmedetomidine. Alternatively, transcranial magnetic stimulation and stellate ganglion block are used (74). Multimodal sleep improves physical and emotional well-being of patients with cancer, and thus has become a commonly used treatment for refractory insomnia in large hospitals.

Although drug therapy has been widely attempted and considered beneficial for sleep, guidelines are still recommended for its short-term use (2–4 weeks), combined with long-term lifestyle changes and immediate management. Drugs cannot reconstruct normal sleep structures while improving sleep quality. Generally, it is helpful for any form of insomnia in the short term. If taken for too long, sleep regulation will be externalized, and once stopped, it is likely to rebound. In addition, long-term use of hypnotic drugs can lead to cognitive deterioration, increased fall and fracture rates (75).

Patients with cancer frequently experience chronic sleep disturbance, and nonpharmacologic therapy may be helpful since it reduces the possible negative effects of long-term drug use. Common methods include CBT, exercise, massage, and relaxation therapy and improve the patient’s sleep environment.

Endogenous cycles in physiology, hormones, and behavioral processes known as circadian rhythms regulate physiological and behavioral activities of each organ to maintain systemic homeostasis. Several key biological processes are regulated by circadian rhythms, including the sleep-wake cycle, food-fast cycle, and activity-rest cycle. Among them, the sleep-wake cycle is most likely the most well-known biological process that adheres to a 24-hour circadian rhythm (95). It provides the foundation for preserving the body’s optimal functioning and is governed by the interaction between endogenous circadian rhythms and steady-state sleep drivers (96). The sleep-wake cycle is strongly bidirectional to the circadian system, with changes in one system affecting the other. Disruption of the sleep-wake cycle, such as chronic sleep deprivation, can disrupt the circadian rhythm. While acute circadian rhythm disruptions can be uncomfortable for a short while, chronic circadian rhythm disruptions can impair the body’s ability to function. This can cause several diseases, such as obesity, cancer, cardiovascular disease, and mental and neurological disorders ( Figure 1 ) (97). Circadian clock genes, including clock, PER, and BMAL1, are impacted by mutations or deletions that impact blood pressure, endothelial function, and glucose homeostasis. Sleep-deficiency-dysregulated CLOCK hypertransactivates ACSL1 to stimulate fatty acid oxidation, mitochondrial respiration, and ATP production, thereby promoting cancer progression (98).

On the other hand, the Circadian clock is essential for cell cycle regulation, and changes in clock function can lead to abnormal proliferation, growth, and DNA damage in cancer cells (99). A large number of epidemiological and animal research have demonstrated that a persistent disruption of circadian rhythm promotes the establishment of cancer characteristics and raises the risk of both breast cancer and prostate cancer (100). Modern culture and lifestyle trends have blurred the lines between day and night and raised the likelihood of disrupted circadian rhythms. These trends include exposure to artificial and blue light at night, longer working hours, shift employment, and an all-weather lifestyle (101). Studies have indicated that women who work night shifts are almost 50% more likely to develop cancer compared to women who do not work night shifts. The International Agency for Research on Cancer reclassified shift work involving circadian rhythm disorders as “possible human carcinogens” (Group 2A) in 2019, based on the research of human and animal cancer mechanisms (102). In 2021, the National Toxicology Program concluded that “continuous night shift work” and “certain lighting conditions” have post-cancer risks (102). Furthermore, the formation of tumors directly weakens the brain’s control over rhythms (51). The disruption of central and peripheral clocks, which causes extensive dysregulation of clock biological processes and melatonin inhibition, is thought to raise cancer risk due to the controlled disruption of circadian rhythms (97). Given these observations, using biological clock components as new targets for chronic diseases such as cancer have attracted widespread attention (103). In theory, there are two pharmacological methods; one is to regulate the core genes of circadian rhythm directly (104), but this is currently still very challenging. Another approach consists of medication formulations targeting proteins—such as REV-ERBα/β, RORα/β/γ, CRY1/2, casein kinase family, and FBXL3—that phosphorylate or degrade clock components. The molecular understanding of circadian rhythms has opened up new frontiers in cancer treatment, and drug regulation of the biological clock and biological clock therapy for cancer may become a new treatment option for better cancer management.

The hypothalamus is an essential component of the brain consisting of multiple nuclei that create and preserve systemic physiological equilibrium. It is critical for regulating sleep/wake behavior, body temperature, sexual behavior, appetite and completion stages of eating, system energy balance, and circadian rhythms (105). Hypocretin/Orexin (HO) neurons are found in the lateral region of the hypothalamus that are highly significant in regulating wakefulness and metabolism. This is because they can receive and integrate signals from the periphery about energy balance and immunological status (106). HO neurons can innervate multiple autonomous output nuclei in the brainstem and can alter the overall energy balance by signaling through the sympathetic nervous system (SNS).Additionally, the Hypothalamus-pituitary axis (HPA) axis is involved in the induction of glucocorticoid production by HO neurons. Glucocorticoids have pleiotropic effects on the immune system and may have peripheral physiological effects on hyperactive states (e.g., anxiety, dread, panic, insomnia). In the context of cancer, many of the physiological signals sensed by hypothalamic neurons are frequently altered; these include inflammatory cytokines/chemokines, including interleukin (IL-6), glucose, and endocrine hormones, such as leptin and ghrelin (107). Increased ghrelin sensitivity, decreased leptin concentrations, elevated levels of IL-6 and blood glucose, and hyperactivity of HO neurons (increased cFos immunoreactivity) were observed in cancer mouse models during the development of sleep debris in the late phase of tumor growth (34).

On the other hand, dual-receptor antagonism promoted deep restorative sleep in tumor-bearing mice, which reduced the HO signal. The aberrant activity of these neuronal populations could be attributed to sleep disruption due to altered immunological, metabolic, or endocrine functioning caused by cancer. McAlpine and colleagues have shown that long, scattered sleep dramatically reduces the number of HO neurons in the lateral hypothalamus, a phenotype associated with arteriosclerosis development. Sleep and memory disorders in patients with cancer may be exacerbated by the dysfunction of melanin-concentrating hormone (MCH)-promoting neurons, which are susceptible to peripheral inputs that become unregulated (106). There is evidence that HO and MCH neurons have inhibitory feedback in vitro. The study found that gabaergic neurons in the preoptic ventrolateral area (Vlpo), Ventral tegmental area dopaminergic neurons, 5-hydroxytryptamine (5HT) neurons in the raphe nucleus, Locus coeruleus (LC) noradrenaline neurons and cholinergic signals in the brainstem are all involved in the development of cancer-related sleep disorders (106). Sleep in patients with cancer can also be affected by astrocytes (108), the astrocyte mediates sensory gain through distinct patterns of astrocytic Ca²⁺ transients, thereby contributing to the overall balance of sleep, wakefulness, and arousal states (109).

Functional alterations of the HPA axis are a common phenomenon in patients with cancer, characterized mainly by elevated corticotropin-releasing hormone (CRH) secretion adrenocorticotropic hormone(ACTH), which leads to abnormally high levels of glucocorticoid and catecholamine. Elevated cortisol can suppress the body’s immune function. According to a large number of studies, dysfunction of the HPA axis in cancer patients, such as pituitary tumors, neurosurgery and radiation therapy of the tumor, can cause symptoms such as depression, anxiety, and sleep disorders (110). Conversely, fatigue, depression, and sleep problems can also trigger HPA axis dysregulation, increase cortisol secretion, and impair the body’s immune function, thereby promoting tumor growth and metastasis. According to Wilkinson et al., lack of sleep is linked to a temporary rise in the autonomic sympathetic adrenal system and HPA activity (111).

Tumors modify the activity of cells in both their immediate and distant environments to avoid detection by the immune system and meet the metabolic needs for growth, multiplication, and metastasis. These cells include T cells, fibroblasts, and macrophages in the liver and brain (46). Chemokines that attract leukocytes, such as C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, CCL7, CCL8, and CCL20 (112), can be released by cancer cells and their microenvironments, along with a variety of growth factors secreted by leukocytes. These factors can frequently reach the entire body through neural and/or humoral pathways to promote abnormal neural activity (113). This can result in fatigue, disruptions to sleep and circadian rhythms, energy balance issues, inflammation, reduced food intake, cachexia/anorexia, and, most commonly, sleep disruption (114). In turn, sleep disorders may disrupt these balances and affect the secretion of factors at specific times. Cancer-induced depression has also been found to be associated with growth hormone and insulin-like growth factor-1 secretion (115).

Adequate sleep is crucial for maintaining strong immune function, which plays a key role in cancer prevention through mechanisms such as immune surveillance (116). Sleep disorders can lead to immune system disorders and abnormal activation of inflammatory responses (117, 118), thereby promoting tumor growth and metastasis. Sleep plays a crucial role in regulating the immune system, with increased production and release of cytokines such as IL-1 and tumor necrosis factor (TNF) during sleep. Sleep also promotes the proliferation of T cells and strengthens the interaction between dendritic cells and T cells. Sleep affects the balance between pro-inflammatory and anti-inflammatory responses. Under normal circumstances, the immune system maintains normal immunological function by balancing T-helper Factor 1 (Th1) and Th2, cell-derived cytokines (Th1 cytokines: IL-2, IFN-γ, and IL-12; Th2 cytokines: IL-4 and IL-10), preferring the antigen delivery pathway (119). During specific periods of nighttime sleep, these cytokines are secreted, such as Th1 activity, which is often enhanced during the first few hours of nighttime sleep, and Th2 activity, which often peaks late in sleep or before awakening (120). This pattern is broken by sleep disorders, with excessive production of cytokines causing immune disturbances, attenuated antigen processing, and antibody formation (121), ultimately causing chronic inflammation. The abnormal activation of the inflammatory response is associated with increased levels of inflammatory factors like TNFγ, IL-6, and c-reactive protein, as well as the activation of inflammatory signals like nuclear factor-kappa (NF-ĸB), signal transducer and activator of transcription 3, and activator protein-1. It is also characterized by abnormal systemic, cellular, and inflammatory transcriptional activity (122). The immune system plays a crucial role in cancer prevention and development through its ability to monitor and eliminate malignant cells. Inflammatory response can promote the development, progression, and recurrence of chronic diseases such as cancer and depression ( Figure 2 ) (123).In turn, anti-cancer therapy of the cancer or the cellular and/or tissue level leads to increase the release of proinflammatory cytokines and dysregulation of the circadian system (124). Increased release of pro-inflammatory factors is associated with increased pain scores in patients with cancer, often associated with severe sleep disorders and depressive states. Likewise, impaired CS can lead to decreased ability to perform daily chores, insomnia, reduced appetite, depression, and fatigue in patients with cancer. Depression can also promote tumor invasion and metastasis by inducing NF-ĸB activation and the HPA axis hyperfunction to coordinate the production of inflammatory mediators and systemic inflammation.

Sleep disturbances affect DNA damage and repair. Sleep deprivation lowers melatonin levels, which increases oxidative damage of the DNA (125). Melatonin is a cancer suppressor and a potent estrogen inhibitor, and its release is dependent on the pineal gland and the suprachiasmatic nucleus. Melatonin acts primarily through the following: it can reduce TOX3 expression by directly activating miR-135b-3p, to thereby inhibit cancer cell migration and proliferation (126); second, melatonin affects is a strong free radical scavenger that impacts quinine reductases to reduce the oxidative damage caused by ROS in tissues (127); finally, melatonin is a strong repressor of transcriptional activity of estrogen-induced estrogen receptor-α (ERα) and inhibits ovarian estrogen production (128), both of which have regulatory roles in the HPG axis. Elevated estrogen levels are generally linked to a higher risk of developing cancer (129). In addition, sleep deprivation can suppress the expression of some genes associated with DNA repair, including RAD50, PARP1, and ERCC6, which eventually leads to the growth of tumors. Conversely, cancer-induced sleep disorders is also associated with oxidative DNA damage and repair ( Figure 3 ).

Other less clear mechanisms include changes in blood glucose levels, amino acid concentrations, and pH levels. So far, the link between sleep cancer and depression is not fully elucidated, and more research is needed.