Melatonin in Integrative Oncology: Biological Mechanisms, Therapeutic Evidence and Implementation Strategies

Melatonin, an endogenous indoleamine primarily synthesized in the pineal gland, has emerged as a promising adjunctive agent within integrative oncology due to its pleiotropic biological actions. Beyond its well-known chronobiological functions, melatonin exerts potent redox-regulatory, anti-inflammatory, oncostatic, and immune-modulating effects that are relevant across multiple stages of carcinogenesis and cancer therapy. Oxidative stress (OS), defined as an imbalance between reactive oxygen and nitrogen species (ROS/RNS) generation and antioxidant defenses, plays a central role in DNA damage, protein adduct formation, and lipid peroxidation, ultimately contributing to mutation accumulation, treatment resistance, and tumor progression. Melatonin modulates these OS-related processes through both receptor-dependent and receptor-independent mechanisms, including mitochondrial stabilization, enhancement of antioxidant enzyme activity, inhibition of pro-oxidant pathways, regulation of cell-cycle checkpoints, and promotion of apoptosis in malignant cells while protecting healthy tissues. Preclinical studies demonstrate synergistic interactions between melatonin and chemotherapy, radiotherapy, targeted agents, and immunotherapies, with consistent reductions in treatment toxicity and improvements in tumor control. Emerging clinical evidence supports its potential benefits in quality of life, sleep regulation, fatigue, and selected oncologic outcomes, although heterogeneity in dosing, formulations, and study design remains a key limitation. At the organizational and system levels, successful integration of melatonin into oncology practice requires interdisciplinary collaboration, standardized protocols, clinician awareness, regulatory clarity, and evidence-based implementation strategies. The aim of this narrative review is to synthesize current molecular, experimental, and clinical evidence on melatonin in integrative oncology, with particular emphasis on redox-related mechanisms, therapeutic interactions, and implementation challenges.