Circadian clock-driven tumor immunoregulation: Mechanistic insights and new perspectives in therapies

Immunotherapy has emerged as a cornerstone of modern oncology; however, its clinical efficacy is frequently constrained by adaptive resistance mechanisms. The circadian clock, a fundamental regulator of metabolism and immunity, governs immune surveillance and tumor microenvironment (TME) dynamics through transcription-translation feedback loops (TTFLs). Disruption of these rhythms-Manifested as clock gene dysregulation, central-peripheral desynchrony, and aberrant metabolic-inflammatory signaling-Creates a permissive environment for tumor immune evasion. Although circadian-targeted therapies show promise, the mechanisms linking circadian disruption to immune escape remain incompletely understood, and the potential of natural products and traditional Chinese medicine (TCM) to modulate these rhythms lacks systematic evaluation. This review critically examines the multilayered mechanisms by which circadian disruption drives immune evasion, specifically targeting the breakdown of immune checkpoint balance and the metabolic-inflammation axis. We further synthesize recent advances in circadian-modulating agents, including natural compounds, and specifically evaluate the alignment between their pharmacokinetic profiles and biological rhythm windows. Finally, we propose an "integrative chrono-immunotherapy" strategy, combining TCM wisdom with emerging technologies such as nanotechnology and multi-omics, to provide a theoretical framework for next-generation precision cancer treatments.