TCM-Driven Circadian Modulation in Cancer: Engineering Spatiotemporal Drug Delivery for Precision Oncology

Circadian disruption constitutes a hallmark of cancer, driving tumorigenesis, progression, and therapy resistance via dysregulation of core clock genes. Emerging evidence indicates that traditional Chinese medicine (TCM), primarily through Chinese herbal medicine (CHM), exerts promising chronotherapeutic effects by modulating tumor-intrinsic circadian rhythms. Bioactive CHM constituents restore the oscillatory expression of clock genes (eg, BMAL1, PER2), thereby resynchronizing cell cycle control, DNA repair, metabolism, and immune surveillance to suppress malignancy. This review provides a comprehensive synthesis demonstrating that CHM not only corrects circadian dysfunction but also uncovers temporal vulnerabilities amenable to precision intervention. To address current translational gaps, we propose an integrated "multi-omics-intelligent delivery-preclinical validation-clinical translation" framework featuring: (1) AI-driven construction of individualized circadian maps to define optimal chronotherapeutic intervention windows; (2) development of tumor rhythm-responsive nanodelivery systems for spatiotemporally precise CHM release; (3) establishment of patient-derived circadian organoid-on-chip and chronotype-matched PDX platforms for multidimensional efficacy-toxicity profiling; and (4) staged clinical trials of chrono-guided CHM nanoformulations. By transforming oncology from static dosing to dynamic circadian modulation, this TCM-inspired paradigm pioneers a spatiotemporal precision medicine strategy that bridges holistic wisdom with cutting-edge chronobiology, thereby advancing the modernization of TCM.