Circadian rhythm in immunotherapy and cellular therapy: impacts on the tumor microenvironment

Abstract

Immunotherapy, including cellular therapy, has emerged as a crucial pillar in cancer treatment, complementing established modalities such as surgery, chemotherapy and radiotherapy. The clinical observation that immunotherapy is effective in only a limited proportion of patients inspires mechanistic research on the complicated regulatory network within the tumor microenvironment (TME). Circadian regulation significantly affects immune cell behavior, including the activity of immune cells and cytokine production, and emerging evidence suggests the key role of circadian regulation in the TME, which subsequently affects the effectiveness of immunotherapy. Results from preclinical and clinical studies indicate that appropriate timing of adoptive cellular therapy and immune checkpoint blockade therapy improves their efficacy. Therefore, understanding the molecular mechanism of the circadian rhythm together with its role in immunotherapy is essential for optimizing cellular function, proliferation and persistence in the TME. Here, we review how circadian rhythms influence immunotherapy and the TME across different stages of tumor progression. Future clinical protocols may integrate concepts of circadian rhythm and immunotherapy to enhance treatment response.

1. Introduction

Circadian rhythms are innate cycles that last approximately 24 hours and regulate physiological and behavioral processes. These rhythms are orchestrated by an internal timekeeping system commonly referred to as the biological clock, which aligns bodily functions with the environmental light-dark cycle [1]. Mechanistically, circadian rhythms are regulated by interlocking feedback loops involving genes such as CLOCK, BMAL1, PER, and CRY and their protein products, which regulate gene expression and downstream physiological pathways [2]. These loops generate self-sustaining oscillations even under constant environmental conditions, although they can be synchronized by several external cues, particularly light, temperature, and feeding schedules [1]. The circadian rhythm in mammals consists of both central and peripheral rhythms. The central rhythm governed by the suprachiasmatic nucleus (SCN) of the hypothalamus synchronizes the body, whereas peripheral rhythms occur in most tissues and organs, regulating processes such as metabolism, hormone release, and cardiovascular function [3]. Coordinating these clocks ensures temporal order across biological systems, optimizing function and survival.

Circadian rhythms, driven by the transcriptional feedback loops of core clock genes, orchestrate a wide array of key physiological processes, such as cell cycle progression, DNA repair, hormone secretion, and especially immune homeostasis. This interplay, often referred to as chrono-immunology, has become a key area of study for understanding how fluctuations in physiological processes across the diurnal cycle influence immune function. Specifically, circadian rhythms modulate immune responses by affecting the expression of clock genes in macrophages, T cells and other immune cells, leading to differential levels of cytokine release, antigen presentation, and cell migration [4]. A comprehensive review revealed that both innate and adaptive immune responses exhibit rhythmic behavior [5]. For example, the circadian regulation of DC activity and T-cell proliferation results in time-of-day-dependent responses to infection and vaccination efficacy. More recent findings have explored the mitochondrial-level regulation of immune cells by the circadian clock, revealing how oxidative phosphorylation and energy production are also time sensitive and further linking the circadian rhythm to the metabolism of immune cells [6]. In addition, mitochondrial isocitrate dehydrogenase is associated with CAR-T-cell function through histone acetylation and metabolism [7]. Circadian rhythm disruptions alter cellular metabolism, DNA repair, and immune function, which can accelerate aging and cancer development [8]. The circadian rhythm intricately tunes the immune system through gene regulation, hormonal balance, and cellular metabolism. Potential therapeutic strategies, including chronotherapy and anti-aging interventions, are proposed to target these interconnected pathways for improved cancer management [8]. Recognizing this link has opened new avenues in chronotherapy, where treatments such as vaccines or immunomodulators may be optimized on the basis of time-of-day administration [9].