Melatonin as a circadian-lifestyle interface in cancer care: biological mechanisms, clinical evidence, and future directions for integrative oncology

Melatonin is an endogenous circadian hormone with pleiotropic antioxidant, immunomodulatory, and oncostatic properties that has emerged as a promising adjunct in cancer therapy, particularly breast cancer. This narrative review summarizes current mechanistic and clinical evidence supporting its role in oncology. Produced from L-tryptophan under circadian control, melatonin acts through MT1/MT2 receptors and receptor-independent antioxidant mechanisms to regulate multiple hallmarks of cancer. It preserves mitochondrial function in normal tissues while promoting apoptosis in malignant cells, suppresses PI3K/AKT and MAPK signaling, inhibits angiogenesis through VEGF and HIF-1α downregulation, reduces epithelial–mesenchymal transition and matrix metalloproteinase activity, and modulates estrogen signaling and epigenetic regulation in hormone-dependent tumors.
Clinical evidence remains inconsistent. Meta-analyses report modest improvements in cancer-related fatigue and quality of life, whereas individual breast cancer trials have shown conflicting findings, emphasizing the need for large, independent, multicenter studies with standardized dosing and longer follow-up. Beyond symptom control, melatonin may counteract circadian disruption, inflammation, and mitochondrial dysfunction that contribute to cancer progression and treatment-related toxicity. Future research should integrate circadian phenotyping, biomarker-guided therapy, wearable monitoring, and combination strategies with immunotherapy to clarify melatonin's role as a safe, multitarget adjuvant in precision oncology.