Table 2.

The brain tumour's time table.

Circadian modulation of …	Cross-cancer discoveries	Pending brain cancer queries
Brain cell activity	▪Circadian rhythms influence neuronal activity and glial cell functions.8 ▪Disruption of circadian rhythmicity described as a carcinogen.16	▪The role of circadian genes and their disruption as propagators of malignant transformation of neural cell types. ▪Temporal dynamics of the interaction between brain cells and immunity.
Tumour cell phenotype	▪Circadian disruptions and clock alterations foster cancer initiation and regulate cancer hallmarks.23 ▪Tumour cell migration and metastatic potential are regulated by circadian rhythms.23 Disruption of circadian rhythms can enhance metastatic behaviour.101 ▪Circadian genes impact brain tumour proliferation, metabolism, and angiogenesis independent of diurnal oscillations.16,47,57	▪Specific mechanisms effectuating circadian oscillations in tumour phenotype to reveal potential targets. ▪The integrity of the tumour clock and the impact of altered clock gene expression on characteristics of different brain cancer types. ▪Comprehensive profiling of circadian changes in immunotherapy target antigen and immune checkpoint expression.
Blood-brain barrier (BBB)	▪Circadian rhythms regulate BBB permeability, temporally affecting e.g., drug delivery.88,89 ▪BBB integrity is challenged by circadian disruption.88 ▪BBB integrity is modulated by brain cancer.102,103	▪The timed accessibility of brain tumours to immunity and (cellular) immunotherapy. ▪Brain cancer dissemination and the formation of brain metastases following circadian oscillations in BBB permeability.
Tumour-immune microenvironment (TIME)	•Tumour immune cell infiltration exhibits circadian variation.87 ▪Disruption of the clock associates with immune cell exhaustion.41 ▪Molecular clock genes can reshape the brain cancer TME to be more immunosuppressive and pro-proliferative.95,104	▪Circadian control of the infiltration into and immune status of cells in the brain TME. ▪Circadian–immune pathway interplay, identification of clock-driven mechanisms in immunosuppression and tumour progression. ▪Potential of synergetic targeting of the clock and cancer immunity.