The suprachiasmatic nucleus (SCN) in the hypothalamus is known as the central circadian pacemaker, which regulates many biological mechanisms in the body. Circadian clock (CC) genes (CCGs) are responsible for regulating numerous cancer-associated biological mechanisms, including the regulation of cell cycle genes, apoptosis, and cell proliferation (Yu and Weaver, 2011). Inherited mutations or environmental disruption of CCGs might negatively influence cellular activities, which can result in cancer. A range of studies have already confirmed the link between variants in CCGs and risks of non-Hodgkin lymphoma, prostate cancer, and breast cancer (Hoffman et al., 2010; Yi et al., 2010; Lin et al., 2011; Zhao et al., 2012; Zhou et al., 2012). Consistently, a potential link between CCGs and brain tumors (BTs) has also been confirmed. It was observed that as compared to adjacent non-glioma cells, period CC (Per) genes including Per1 and Per2 were found to be underexpressed in glioma cells (Xia et al., 2010). A similar trend has also been observed in the case of other CCGs, including cryptochrome (CRY) genes (Cry1 and Cry2) (Madden et al., 2014).

BTs involve a diverse group of central nervous system (CNS) neoplasms. Depending on the pathological diagnosis, around 100 different types of BTs have been recognised. Depending on whether these tumours originate in the brain or merely spread to the brain from other parts of the body, they can generally be grouped into primary or secondary BTs. Malignant gliomas represent almost half of all primary BTs, while astrocytomas represent over three-quarters of all gliomas. In addition, malignant gliomas represent 28% of all BTs and 2% of all cancer types. Global age-adjusted occurrence of all gliomas ranges from 4.67 to 5.73 per 100,000 people (Ostrom et al., 2014; Weller et al., 2015; Davis, 2018; Louis et al., 2021). Glial tumours occur from glial precursor cells, oligodendrocytes or astrocytes (Liu et al., 2011; Lee et al., 2018). Gliomas can be classified as grade I (least aggressive) to grade IV (most aggressive), depending on the molecular markers and diverse histological features including intratumoral necrosis, vascular proliferation, nuclear polymorphisms, and cellular heterogeneity.

Increasing evidence suggests that the deregulation of CCGs is associated with gliomagenesis. CCG expression levels in the high-grade glioma were substantially higher as compared to non-gliomas or low-grade gliomas. Moreover, disrupted CC can lead to impaired stemness of glioma stem cells (GSCs) in glioblastoma multiforme (GBM) (Huang et al., 2019). In a study, Petkovic et al. characterized glioma-associated dysregulation of CC and CCGs. These researchers demonstrated that an increased level of dysregulation in gene expression is present in GBM as compared to low-grade glioma, which further suggests the link between the differentially expressed clock-controlled genes and survival of the patients in case of both GBM and low-grade glioma (Petkovic et al., 2023a). Patients with BTs might experience disturbances in their CC, which can be manifested by disruptions in activity patterns, abnormal mental states, and sleep disorders. Therefore, assessment of the link between CCGs and BTs can help in understanding how CC disruptions can affect the quality of life of patients with BTs and progression of the disease (Hou et al., 2024). In a study, Hou et al. (2024) explored the link between core CCGs and multiple characteristics of BT pathogenesis. In order to carry out comprehensive analyses, they used various datasets including mutation, methylation, gene expression, and clinical data from patients with brain tumor. The researchers studied the impact of CCGs in the development of lower grade glioma and observed that certain genes including RORβ, NPAS2, and CRY1 were linked with elevated or reduced risk of lower grade glioma (Hou et al., 2024). The researchers also assessed the link between CCGs and immune cell infiltration, which revealed a positive relationship with infiltration of B cells and CD8+T cells and a negative relationship with macrophage infiltration. Moreover, the researchers detected the main mutated CCGs, including Clock, BMAL1, BMAL2, and Per2, and their possible interaction with various other CNS-related genes. It was concluded that CCGs have a significant contribution in immune responses as well as tumorigenesis in patients with lower grade glioma, which also requires more investigations.

CC orchestrates various physiological mechanisms by modulating cell functions and signalling pathways. This role further extends to the differentiation, behaviours, and functions of immune cells associated with innate and adaptive immunity systems (Wang Q. et al., 2022; Cermakian and Labrecque, 2023). There is a growing number of studies focusing on the CC-mediated regulation of transcriptional processes that determine gene expression in key signalling pathways, including Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (Dong Q. et al., 2019; Habbel et al., 2020). Disrupted circadian rhythms can worsen the malfunctioning of these regulatory mechanisms, potentially resulting in uncontrollable inflammatory responses and diseases (Lin et al., 2024). It is now well-known that circadian rhythms have a significant influence on numerous parameters in the immune system including the cytokine levels and the number of circulating hematopoietic cells (Cermakian et al., 2013; Nakao, 2014). Various studies have already demonstrated that CC plays an important role in the regulation of cytokines (Bechtold et al., 2010; Arjona et al., 2012; Scheiermann et al., 2013). In a study, Keller et al. (2009) observed that macrophages derived from the mouse peritoneal cavity, lymph nodes, and spleen contain intrinsic CC that operate independently as well as other acquired and innate immune cells. The researchers also reported that macrophages derived from mouse spleen induced with LPS at different time points showed circadian rhythms in the secretions of various cytokines including interleukin-6 and tumor necrosis factor alpha (TNF-α), which indicates that macrophage-intrinsic CC might regulate these oscillations (Keller et al., 2009).

It has been observed that CD8⁺ T cells also express CCGs and their counts show 24-h rhythms in the blood and in secondary lymphoid organs, which was found to rely on the CC present in these cells and on hormonal rhythms. Furthermore, the extent of responses mediated by CD8⁺ T cells to antigen presentation can vary depending on the time of day, a circadian rhythm reliant on the CD8⁺ T cell clock (Cermakian and Labrecque, 2023). Circadian control of immune modulation has a significant contribution in tumor immunosurveillance and host defence (Fortin et al., 2024). In a study, Wu et al. (2019a) reported that immune checkpoint expression and immunoregulatory mechanisms can be affected by the disturbance in circadian rhythmicity in tumour-resident cells to benefit the tumor.

Crespo et al. (2012) observed a differential pattern of CCG expression in glioma cells in comparison with their paired neighbouring normal brain tissues, which suggests an asynchrony amongst the CCs. An altered chromosomal number was also detected by the researchers utilizing single nucleotide polymorphism array. In addition, the amplification of chromosomal segment 4q12 was identified, where the mammalian CCG is situated. The altered copy number on the DNA level had an impact on the mRNA levels, which further indicates an important link with the disease pathogenesis (Crespo et al., 2012). In GSCs, it has been observed that downregulation of the Bmal1 gene stimulated apoptosis as well as cell cycle arrest (Dong Z. et al., 2019). Epithelial-mesenchymal transition (EMT) is a process that mediates GSCs populations, invasiveness, and tumor cell metastasis (Hakami et al., 2024a). The targeted phase activation in the core CCG Per2 might serve as a potential target for therapies that might inhibit EMT, limit tumor metastasis, and minimize GSCs (De et al., 2020). The expression of the Per2 gene was found to be enriched within C6 glioma tumor spheres but not in monolayer cell culture, suggesting that cell interactions or tumor microenvironment (TME) permit circadian timing (Wang and Chen, 2022). The GBM heterogeneity may be partly bestowed by the phenotypic plasticity indigenous to cancer stem cells mediating adaptability needed for tumor growth (Safa et al., 2015).

The most malignant glioma (grade IV) is known as GBM, which is the most aggressive type of BT and patients with GBM have an average survival of 15 months despite multimodal therapies including chemotherapy, radiation therapy, and surgery (Weller et al., 2015; Ostrom et al., 2019a; Petkovic et al., 2023b). Numerous novel therapies have been developed to treat GBM, however after diagnosis still less than 5% of patients with GBM survive for 5 years (Davis, 2016). In recent times, several researchers suggested improving the delivery of anticancer drugs via timing it to the daily rhythms of the patients (Dakup et al., 2018). CCs primarily organize the behavior and physiology of humans via producing daily rhythms in various physiological mechanisms, including endocrine systems, digestive and cardiovascular mechanisms, body temperature cycles, locomotor function, behaviour, sleep/wake cycles, and immune and metabolic activities with an intrinsic 24-h period oscillation. This approach has recently been utilized in the treatment of BTs owing to a differential response to bortezomib, a proteasome inhibitor, in a murine model. On the other hand, temozolomide (TMZ) chronotherapy in murine and human GBM cells in culture was found to be reliant on CCG expression.

CC plays an important role in regulating various metabolic pathways including glycolysis. Thus, disruption of circadian rhythm is linked with metabolic imbalance (Yoo et al., 2020). Indeed, glucose homeostasis is regulated via the CC present in the SCN and peripheral clocks present in the white adipose tissue, pancreas, muscle, and liver. Glucose present in blood is mainly obtained through diet during the active phase and predominantly from endogenous glucose generation in the liver during the resting phase. The uptake of glucose shows a 24-h rhythm, along with the highest level at the beginning of the active phase and the lowest level at the beginning of the passive phase (Kalsbeek et al., 2014; Zlacká and Zeman, 2021a). Chronodisrupted individuals exhibit a disturbed rhythm in plasma glucose as well as insulin levels. In addition, genetic studies revealed that there is a link between PER2 and CRY and blood glucose level (Gachon et al., 2017).

Mitochondria has a significant contribution in oxidative phosphorylation. It has been observed in rat hepatocytes that the shape and volume of mitochondria can oscillate under dark and light conditions. Hepatocytes derived from mice at different times during the day showed increased levels of respiration during the dark as compared to the light phase in the presence of pyruvate (Zlacká and Zeman, 2021b). In a study, Schmitt et al. (2018) reported that CC-regulated oxidative phosphorylation was reliant on dynamin-related protein 1 (DRP1). DRP1 activities are controlled by phosphorylation at serine residue 637 (Ser637) and following inactivation or activation. Phosphorylation of DRP1 at Ser637 exhibits 24-h rhythms along with the peak level at CT12, which is beginning of the subjective night (Schmitt et al., 2018). On the other hand, oxidative stress is linked with the pathogenesis of various diseases and the interaction between CCs and oxidative stress is evident, where disrupted circadian rhythms can modify redox homeostasis resulting in oxidative stress and increased generation of reactive oxygen and nitrogen species might trigger circadian oscillations (Wilking et al., 2013; McClean and Davison, 2022).

Circadian rhythm can also affect the pharmacodynamics and pharmacokinetics of anticancer therapies. Knowledge regarding the processes underlying chemoresistance can facilitate identification of a group of patients who might benefit from chemotherapy and circumvent overtreatment (Brahimi-Horn et al., 2012). In a study, Fang et al. (2015) reported that degradation of CCG CRY2 Is associated with the chemoresistance of colorectal cancer. In another study, Xu et al. (2018) revealed that CCG CLOCK is strongly linked with chemo-resistance of ovarian cancer cells. Increased expression of CLOCK endowed resistance of ovarian cancer cells to cisplatin treatment. It was observed that CLOCK-induced increased level of drug resistance genes (such as P-glycoprotein (P-gp)), autophagy, and ATP binding cassette subfamily C member 2 may facilitate the aforementioned process (Sun et al., 2017). In this review, an overview of BTs, the genetics of the circadian clock, and the connection between pathological disruptions of the CCGs and BT development have been discussed. Moreover, potential pharmacological interventions to modulate CCGs in BTs have also been reviewed.

BTs including both primary and secondary tumours are graded from I to IV according to World Health Organization (WHO) (Kheirollahi et al., 2015). Grade I tumors exhibit a slow proliferative rate, which can be treated by surgical resection. Grade II tumours are low-grade gliomas that show less proliferation activity; however they show greater infiltration activities and can even progress to higher-grade tumors. Patients with grade II tumors have an overall over 5 years survival rate. Surgery can be carried out to treat grade II tumors, however these tumors frequently recur more aggressively (Wirsching and Weller, 2017). On the other hand, grade III tumors show an increased rate of infiltration and high proliferative activity. In addition to this, Grade III tumors are histologically malignant and patients have an overall 2–3 years survival rate, which can be treated with chemotherapy and/or adjuvant radiation therapy. The most vigorous proliferation activities are exhibited by life-threatening grade IV tumors, which can even invade adjacent tissues. Grade IV tumors show abrupt mitotic activity, which needs more aggressive therapies containing chemotherapy as well as adjuvant radiation therapy (Louis et al., 2016). Gliomas and neuroepithelial tumors are the most common form of primary BTs, whereas meningiomas are the most common secondary BTs (Baldi and Loiseau, 2012). Both males and females are equally prone towards BTs, however females tend to develop meningiomas more than males (Sun et al., 2015; Rasheed et al., 2021). In the USA, primary BTs are one of the top 10 causes of tumor-associated deaths as per the American Cancer Society. Around 13,000 BT-associated deaths are reported every year in the USA. In addition, 1 in 1,300 children aged below 20 is diagnosed with BT (Baldi and Loiseau, 2012). Various factors (for example-genetic risk factors, exposure to ionizing radiation and pesticides) are responsible for BTs and currently used therapies in the treatment of BTs have poor therapeutic efficacy and serious side effects (Ostrom et al., 2019b). Furthermore, the blood-brain barrier (BBB) poses numerous challenges in the delivery of anticancer drugs because of the tight junctions of the BBB, which severely restrict the delivery of drugs into the brain at the targeted tumor sites (Rasheed et al., 2021; Kaur et al., 2023).

Circadian disruption has been identified by WHO as a possible carcinogen (Munteanu et al., 2024). CC alterations have also been associated with elevated risk of various cancers including lung, ovary, pancreas, liver, colon, breast, and prostate cancers. In addition, a deficiency of circadian control is associated with insufficient efficacy of anticancer therapies and early mortality of cancer patients (de Assis and Oster, 2021). Interestingly, cancer, diabetes, obesity, mood disorders, and sleep are associated with the alterations in the CC caused by not getting enough sleep, eating at night, or even chronic jet lag (de Assis and Oster, 2021). Functions and expressions of various oncogenes and tumor suppressors in both tumor tissues and host are substantially changed via CC disruptions caused by environmental and genetic factors. Moreover, CC disturbances can reposition the host immune and metabolism systems, which can mediate an immunosuppressive TME in various types of cancers (Lee, 2021). Recently, a direct link between the core CC and apoptosis has been demonstrated. According to the clock status and cellular context, circadian factors can both restrict and mediate apoptosis, as was observed with the regulation of cell cycle. In terms of mediating cell death, PER1 and cryptochrome (a photoreceptor associated with the CC) can influence the extrinsic TNF-α-dependent pathway and the intrinsic apoptotic pathway, respectively (Shafi and Knudsen, 2019). Moreover, at least 14 core CCGs form several chain feedback loops that mediate the CC along with its intrinsic circadian rhythmicity. Numerous studies have already demonstrated a strong link between the risk of various cancer types CCG dysfunctions caused by epigenetic modification, deletions, single nucleotide polymorphisms, and deregulation to the impact that CCGs have in the onset and metastasis of cancer (Mocellin et al., 2018; Liu et al., 2022; Zhang et al., 2024).

Research on Drosophila mutants with aberrant behavioral rhythms led to the discovery of CCG, period (per). Indeed, these investigations laid the basis for knowledge regarding the molecular foundation of the CC, as the Per gene regulates the PER protein and CC, where PER protein itself controls the expression of per gene. Interestingly, the first known mammalian central CCG, Clock, was revealed by extending the investigations in Drosophila, which was further evaluated in forward-genetic analysis in mice with aberrant CCs. The PER protein in Drosophila was found to have common features with the CLOCK protein in mice, for example, a PAS domain (for Sim, ARNT, and Per). Nonetheless, the CLOCK and BMAL1 work together to regulate CCs, they also contain bHLH domains that facilitate the binding of DNAs directly with the regulatory elements (E-boxes) on rhythmic genes to regulate their transcription (Cox and Takahashi, 2019). The main targets of CLOCK:BMAL1 involve various other core CCGs that encode the CRY proteins (encoded by Cry1 and Cry2 genes) and PER proteins (encoded by Per1, Per2, and Per3 genes). These negative controllers heterodimerize then translocate into the nucleus, where they inhibit their own gene transcription through direct interaction with the CLOCK:BMAL1 (Michael et al., 2017; Rosensweig et al., 2018). Furthermore, the mRNA expressions of Cry1/2 and Per1/2/3 are controlled through various processes (Kojima et al., 2011). For example, degradations of CRY and PER proteins are controlled via the F-box proteins (including FBXL21 and FBXL3), casein kinase 1 epsilon (CK1ε) as well as delta (CK1δ), serine/threonine kinases, and various other proteins (Hirano et al., 2013; Yoo et al., 2013; Narasimamurthy et al., 2018).

Interestingly, when negative transcriptional feedback as well as post-translational and post-transcriptional regulation of CRY and PER is adequate to reduce the levels of PER/CRY proteins in the nucleus, suppression is relieved and CLOCK:BMAL1 mediates transcription of the Per and Cry genes (Takahashi, 2016a). A range of core mammalian CCGs, feedback loops, and various other genes have been discovered since the initial discovery (Figure 1). In the case of the second feedback loop, BMAL1 and CLOCK activate the transcription of genes for the nuclear receptors REV-ERBβ and REV-ERBα, which were found to compete with the retinoic acid-related orphan receptors (ROR-α, β, and γ) for ROR-binding sites on the BMAL1 gene, which also provide both negative (REV-ERB) and positive (ROR) transcription regulation (Zhang et al., 2015). On the other hand, the third feedback loop includes the nuclear factor, interleukin 3 regulated (NFIL3) protein and D-box binding protein (DBP), which were found to be controlled by CRY1 and CLOCK:BMAL1, and bind with the D-box elements on the promoters of various CCGs including ROR-α and β (Stratmann et al., 2010). Collectively, CC is regulated by these feedback loops, which are controlled by transcriptional, post-transcriptional, and post-translational regulatory mechanisms that are adequate to maintain CCs (Golombek and Rosenstein, 2010a; Takahashi, 2016a; Cox and Takahashi, 2019).

Oscillations of CC are seen in nearly all tissues (including glial cells), which play crucial roles in brain functions and development (Rojo et al., 2022). Since most of the malignancies in the brain initiate from glial cells or their precursors, therefore it is important to know the physiological functions of CC (Arafa and Emara, 2020). In the brain, astrocytes are the most plentiful population of glial cells (Allen and Eroglu, 2017). Glial cells are important for nervous system health because of their crucial trophic and metabolic support to neurons (Murphy-Royal et al., 2017). In addition, astrocytes showed rhythmic alterations governed by CCGs in vitro in mouse cortical astrocyte cultures. Oscillations of Per1, Per2, Clock, and IP3-dependent calcium signalling were found to control the daily rhythms of ATP secretion in astrocytes (Marpegan et al., 2011). The core CC protein BMAL1 regulates neurotrophic functions and astrocyte activation through a cell-autonomous mechanism, whereas reduced BMAL1 levels trigger astrogliosis (Lananna et al., 2018). The generation of hypoxic inducible factor 1α (HIF1α) was found to be induced in the brain by hypoxia in ependymal, astrocytes, neurons, and perhaps endothelial cells (Jolly et al., 2011a). It has been identified that ROR-α is a target for HIF1α (Jolly et al., 2011a). An increased level of ROR-α was detected in vitro during hypoxia in primary mouse astrocytes, which further resulted in the hypoxic inducible factor 1α downregulation (Jolly et al., 2011b). Glutamate uptake levels are influenced by Npas2, Per2, Clock along with no noticeable circadian variation. Interestingly, astrocytes in the SCN regulated behaviour and daily rhythms in the SCN, while Bmal1 deletion in astrocytes extended the circadian period of rest-activity rhythms in mice (Tso et al., 2017a). Collectively, these findings indicate the crucial roles of CC in astrocyte functions (Quist et al., 2024).

Microglia are the major immune cells of the CNS that eradicate dead cells in adult CNS and the developing brain to mediate normal brain development (Prinz et al., 2019). They have a significant contribution in the development and preservation of synapses. In addition, microglia contain a CC that controls their immune activity (Fonken et al., 2015). Disturbances of CCGs in microglia can enhance chronic neuroinflammation which was found to be linked with the early onset of Alzheimer’s Disease (Ni et al., 2019). Obesogenic diets were found to affect the expression of CCG in microglia, which resulted in chronic microglial activation in rat models (Milanova et al., 2019). The molecular clock REV-ERBα plays an important role in establishing a balance in microglial phenotype and averting neuroinflammation. Synaptic phagocytosis increases because of the low REV-ERBα levels, whereas REV-ERBα loss can lead to neuronal dysfunction and spontaneous neuroinflammation (Griffin et al., 2019; 2020). Oligodendrocytes are neuroglial cells that have a significant contribution in signal conduction in the CNS (Kuhn et al., 2019). At present, there is no strong evidence that oligodendrocytes have an internal CC. On the other hand, rhythmic expressions of Per2, Bmal1, and Rev-Erbα have already been demonstrated in mice. Furthermore, Bmal1 deletion showed a strong link between its expression and oligodendrocyte precursor cell-cycle regulation, cell proliferation, and morphology. Genes specific to oligodendrocytes oscillate throughout the sleep-wake cycle in mouse models. Thus, it is believed that oligodendrocytes might possess a functional CC. Since numerous studies have already demonstrated that CC regulates important events in functions of glial cells, thus disturbances in CC can lead to various neurological conditions (Quist et al., 2024).

The close link between cancer and CC disruptions has already been demonstrated by various studies (Figure 2). Dysregulated expression of CCGs in various types of tumors has also been revealed (Shilts et al., 2018). There is a presence of a mutual regulatory process between CCGs and cancer genes. Several tumor suppressor genes and oncogenes (for example-tumor suppressor gene p53 and oncogene c-Myc) are regulated by CC, as well as the core CCGs are controlled by tumor suppressor genes and oncogenes, which are associated with malignancy and tumor onse (Huber et al., 2016; Shostak et al., 2016; Li, 2019). CC also controls gene rhythms linked with metabolic activity, endocrine functions, and metabolic functions as well as homeostasis of the endocrine system, which have a significant contribution in the development of tumors (Blask et al., 2014; Gamble et al., 2014; Aviram et al., 2016). Aberrant circadian rhythms mediate the malignant advancement of tumors via the deteriorating the immune system. As the immune system is crucial in limiting the development of tumors, therefore disturbed biological rhythms can affect the body’s innate and acquired immunity as well as mediate tumor immune escape via immune checkpoints (He et al., 2018; Wu et al., 2019a; Aiello et al., 2020; Hadadi et al., 2020).

SCN is an important bilateral structure located in the hypothalamus, which is the central pacemaker of the circadian timing system, which can receive (Duhart et al., 2017). The circadian cycles repeat with a period close to 24 h, even in the absenteeism of external stimulations, and it can adjust the alterations in the light-dark cycle via a certain synchronization cascade (Golombek and Rosenstein, 2010b). Various behavioral and physiological variables including neurological functions and hormone levels are controlled by the CC, which also have a significant contribution in the regulation of circadian rhythm (Musiek and Holtzman, 2016). In addition, misalignment and circadian disturbances between the CC and the environmental cycles have been linked with fatigue and mood disorders (Duhart et al., 2013b; Bedrosian and Nelson, 2017). Within the SCN, glial cells are associated with synchronization mechanisms (Lavialle et al., 2001; Girardet et al., 2010; Duhart et al., 2013b) and circadian timekeeping (Barca-Mayo et al., 2017; Brancaccio et al., 2017; Tso et al., 2017b), and are also regarded as mediators between the circadian pacemaker and proinflammatory signals (Duhart et al., 2013a). Among the proposed mechanisms for glial cells-mediated modulation of the circadian pacemaker, the modulation of glutamate concentrations via SCN astrocytes is crucial for the appropriate CC functioning (Leone et al., 2015; Brancaccio et al., 2017).

Elevated levels of glutamate are characteristic features of gliomas, which indicates that a disequilibrium in proper glial cell functions takes place in malignant tissues, which might affect both synchronization and timekeeping mechanisms of the clock (Robert and Sontheimer, 2013). Moreover, various molecules associated with immune responses including CCL2, IL-1β, and TNF-α can influence the master circadian oscillator (Leone et al., 2012; Duhart et al., 2016). Gliomas can markedly change the TME in which they develop, and molecules associated with the immune responses have been confirmed to have a significant contribution in the progression of tumors (Christofides et al., 2015). In view of the occurrence of fatigue and sleep alterations as common symptoms of gliomas, the disruption in anatomical features of CC and optic tract in hypothalamic gliomas, and the changes in the molecules pertinent for the circadian pacemaker in TME (Duhart et al., 2017).

Among the BTs, GBM is the most complex, aggressive, and treatment-resistant cancer. Despite global efforts, still insignificant improvement has been achieved in the improvement of overall survival of patients with BTs, particularly in the case of GBM. Growing evidence regarding gliomas including GBM indicates the significance of modulation of CCG in cancer biology. These studies also revealed how tumor cells can disrupt CCGs to safeguard their survival. It has also recently been demonstrated in the case of gliomas (especially GBM) that CCGs should be targeted for the development of novel therapies or to ameliorate the current treatments that impair and abolish tumor growth. Circadian rhythms present in cells are considered in the case of chronotherapy in order to estimate the optimum time for drug administration to enhance the therapeutic outcome as well as reduce undesirable side effects. However, still more studies are still required to answer several questions in this field including whether the circadian rhythm alteration is a crucial physiological factor in the genesis of glioma, whether the regimen of treatment is modified as per the CCG of the patient, and how to precisely detect CCGs of patients during clinical therapies. The presence of BBB is a major challenge in BT treatment, since BBB is composed of various transport systems and molecular components which can hinder the entry of various drugs in brain (Bhowmik et al., 2015; Arvanitis et al., 2019). Thus, this challenge also need to be carefully considered while developing novel therapies to treat BT.

Recent study findings have revealed that how tumor cells can reprogram CC to ensure their survival, which indicate the significance of CC modulation in case of cancer biology. There is a growing need for the targeting of CCGs to prevent and/or treat diseases particularly BTs, owing to the recent advances in CCG research and findings regarding the link between the CCG and molecular mechanisms controlling various physiological and pathological mechanisms. As mentioned above, dysregulation of CCGs is closely connected with the onset and progression of BTs. Since BTs including GBM show resistance to typical treatments with a bad prognosis, thus circadian consideration might prove beneficial in the case of treatments. In spite of significant findings revealed by various in vitro and animal studies, a low number of clinical studies have been carried out in this field. Therefore, more clinical trials are required to determine the optimum administration methods of drugs discussed above. More studies are also required to answer several questions in this field, such as how to precisely detect the patient’s CC status during clinical treatment and whether a customized treatment regimen is required based on the CC of the patient.