Melatonin in lung cancer: integrating molecular mechanisms, tumor microenvironment regulation, apoptotic signaling, and therapeutic opportunities

Abstract

Lung cancer (LC) remains a major cause of cancer-related mortality, and current therapeutic strategies are frequently limited by treatment resistance, tumor heterogeneity, and adverse effects. Although apoptosis is a critical mechanism underlying the anticancer activity of chemotherapy and radiotherapy, accumulating evidence indicates that cancer cell fate is also regulated by interconnected processes, including oxidative stress responses, mitochondrial dysfunction, inflammation, immune modulation, and tumor microenvironment (TME) interactions. Melatonin (MLT), an endogenous indoleamine involved in circadian regulation, has emerged as a potential anticancer molecule due to its pleiotropic effects on tumor biology. In LC models, MLT has been shown to modulate apoptotic pathways through regulation of mitochondrial signaling, reactive oxygen species homeostasis, cytochrome c release, Bcl-2 family proteins, and caspase activation. Beyond apoptosis, MLT influences cancer progression by regulating proliferation, invasion, angiogenesis, inflammatory signaling, and interactions within the TME. Furthermore, emerging evidence suggests that MLT may enhance the sensitivity of LC cells to conventional therapies, including chemotherapy and radiotherapy, through modulation of cellular stress responses and death pathways. This review summarizes the molecular mechanisms underlying the anticancer effects of MLT in LC, with particular emphasis on apoptotic regulation, redox signaling, genomic mechanisms, TME modulation, and therapeutic implications. However, despite promising preclinical findings, clinical evidence supporting MLT as an adjunctive anticancer therapy remains limited, highlighting the need for well-designed clinical studies to determine its safety, efficacy, and translational potential.