Temporal dynamics in cancer immunotherapy: the interplay between circadian rhythms, tumor microenvironment, and immune checkpoint blockade

The tumor microenvironment (TME) is a highly intricate and dynamic system composed of various cellular and non-cellular components, which plays a crucial role in regulating key biological processes such as tumor initiation, progression, and therapeutic response. Recent studies have uncovered a complex regulatory network between the circadian rhythm system and TME, which significantly impacts the clinical efficacy of immune checkpoint inhibitors (ICIs). This review systematically delineates the multi-level regulatory mechanisms by which circadian rhythms influence key components within the TME, including tumor cell biological characteristics, immune cell functional states, angiogenesis processes, and cancer-associated fibroblast activity. It deeply analyzes the systemic impact of the TME on ICI treatment efficacy via immunosuppressive networks, immune checkpoint molecule expression, T cell functional states, and drug bioavailability. The review underscores the central role and clinical significance of circadian rhythms in regulating immune checkpoint molecule expression, immune cell function, ICI drug pharmacokinetics, and TME homeostasis. Based on these research advancements, this paper systematically presents ICI treatment optimization strategies grounded in circadian rhythm dynamics and TME characteristics, encompassing time-dependent dosing regimens, combination therapies targeting the TME, circadian rhythm modulation methods, and precision personalized treatment approaches. Additionally, it offers a systematic outlook on the research frontiers and clinical translation prospects in this field, encompassing multi-omics integrated analysis of circadian regulatory networks, artificial intelligence (AI)-based precision chronomedicine strategies, novel chronotherapeutic approaches, and standardized clinical translation systems. This review establishes a crucial theoretical foundation for understanding the circadian rhythm-TME-ICI interaction network and optimizing cancer immunotherapy strategies.