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

Feb 25, 2026Journal of the National Cancer Center

How daily body rhythms interact with the tumor environment and immune therapy over time

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Abstract

Circadian rhythms may significantly influence the effectiveness of immune checkpoint inhibitors (ICIs) in cancer treatment.

The tumor microenvironment (TME) plays a critical role in tumor development and response to therapies.
Circadian rhythms are linked to variations in tumor cell characteristics, immune cell activity, and angiogenesis within the TME.
ICIs' effectiveness may be affected by the interplay between circadian rhythm dynamics and the immunosuppressive environment of the TME.
Optimizing ICI treatments could involve time-based dosing strategies and therapies that align with circadian rhythms.
Future research may focus on integrated approaches combining multi-omics analysis and AI to enhance cancer treatment outcomes.

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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.

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

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