Integration of circadian rhythms and immunotherapy for enhanced precision in brain cancer treatment

Abstract

Circadian rhythms significantly impact (patho)physiological processes, with disruptions linked to neurodegenerative diseases and heightened cancer vulnerability. While immunotherapy has shown promise in treating various cancers, its efficacy in brain malignancies remains limited. This review explores the nexus of circadian rhythms and immunotherapy in brain cancer treatment, emphasising precision through alignment with the body's internal clock. We evaluate circadian regulation of immune responses, including cell localisation and functional phenotype, and discuss how circadian dysregulation affects anti-cancer immunity. Additionally, we analyse and assess the effectiveness of current immunotherapeutic approaches for brain cancer including immune checkpoint blockades, adoptive cellular therapies, and other novel strategies. Future directions, such as chronotherapy and personalised treatment schedules, are proposed to optimise immunotherapy precision against brain cancers. Overall, this review provides an understanding of the often-overlooked role of circadian rhythms in brain cancer and suggests avenues for improving immunotherapeutic outcomes.

Keywords: Adoptive cellular therapy; Brain cancer; Chronomodulated therapy; Circadian rhythms; Immune checkpoints; Immune system; Immunotherapy.

Fig. 1

Overview of the core clock machinery in the brain. The transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-Like 1 (BMAL1) form heterodimers that bind to enhancer box (E-box) elements, thereby driving the transcription of cryptochrome (CRY1/2), period (PER1/2/3) and tyrosine-protein kinase transmembrane receptor RORα/β/γ and REV-ERBα/β.^, PER/CRY heterodimers accumulate to inhibit BMAL1/CLOCK activity. Concurrently, RORα/β/γ and REV-ERBα/β compete for binding to ROR response element (RORE) on the BMAL1 promoter, respectively activating or inhibiting its transcription. This intricate feedback loop generates rhythmic fluctuations in clock-controlled gene expression within 24-h cycles.^, The molecular clock is present in virtually all cell types in the human body, including neurons, astrocytes, microglia, and oligodendrocytes and drives daily fluctuations in their morphology and functionality.

Fig. 2

Immunotherapeutic strategies to target brain cancer. Several immunotherapeutic strategies have been developed over the past decades, aiming to generate an anti-tumour response from the immune system. Both oncolytic virus therapy and dendritic cell vaccine activate the adaptive part of the immune system via dendritic cells. Oncolytic virus therapy relies on in vivo activation of dendritic cells, whereas dendritic cell vaccine therapy involves training dendritic cells ex vivo from monocytes. In contrast, CAR T/NK cell therapy uses engineered receptors that enable these cells to precisely target and attack the tumour. Immune checkpoint inhibitor therapy does not focus on training the immune system but instead removes immunosuppression in the TME by blocking one or more inhibitory checkpoints. Made with BioRender. CAR: chimeric antigen receptor; TME, tumour microenvironment.

Fig. 3

Integration of circadian rhythms and immunotherapy for enhanced treatment of brain tumours. Circadian rhythms dictate various processes that affect the efficacy of brain cancer treatment. The immune cells exhibit circadian changes in activity, sensitivity, immune checkpoint expression, and infiltration rates. Similarly, circadian rhythms dictate the permeability of the BBB. On the other hand, the malfunctioning of the circadian clock in brain cancer boosts cancer progression. Simultaneously, these changes can attract immunosuppressive microglia, further shaping an immunosuppressive TME. Taken together, circadian rhythms may provide an optimal time-window for administering chronomedicine, targeting the clock, or immunotherapeutic interventions. Made with BioRender. BBB: blood-brain barrier; CAR: chimeric antigen receptor; DC: dendritic cell; ICI: immune checkpoint inhibitors; NK: natural killer; RORE: ROR response element; TME: tumour microenvironment.