Circadian Rhythms in Cancer: Mechanistic Insights, Chronotherapeutic Strategies, and Translational Challenges

Circadian rhythms orchestrate essential physiological functions, including cell proliferation, DNA repair, immune surveillance, and metabolism, and their disruption has been increasingly associated with tumorigenesis, disease progression, and treatment resistance. This review synthesizes recent mechanistic insights into how core circadian regulators-such as BMAL1, PER, and CRY-interact with key oncogenic pathways, including p53, MYC, and PI3K/AKT, to shape tumor behavior. Preclinical studies demonstrate time-of-day-dependent variation in the efficacy and toxicity of chemotherapy, radiotherapy, and targeted therapies; however, clinical translation remains limited, constrained by heterogeneous circadian phenotypes, logistical challenges, and the absence of standardized rhythmic biomarkers. We critically evaluate emerging technologies, such as organ-on-a-chip systems, wearable circadian monitoring devices, and artificial intelligence (AI)-guided dosing models, that hold promise for enabling personalized chronotherapy. Despite growing interest, substantial gaps remain in validating these approaches across diverse patient populations and tumor types. We propose that advancing chronotherapeutic strategies will require robust rhythm quantification tools, integration of multi-omics analyses, and circadian-aware clinical trial designs. Ultimately, aligning treatment with biological time could unlock new therapeutic windows and improve cancer outcomes, but successful implementation will depend on bridging molecular chronobiology with precision oncology.