Natural Killer Cell Cytotoxicity: STAT3 Interactions with NF-<b>κ</b>B Dimer Composition Modulate Mitochondrial Melatonergic Pathway: Tumor, and Viral Infection Treatment Implications<sup>#</sup>

As natural killer (NK) cells eliminate cancer cells and virus-infected cells, as well as modulate various other medical conditions, including aging-associated conditions such as neurodegenerative disorders, understanding NK cell regulation is of considerable clinical importance. This article reviews the role of circadian processes (melatonin and the cortisol system), aryl hydrocarbon receptor, and vagal nerve in the modulation of NK cell function, highlighting the importance of the endogenous mitochondrial melatonergic pathway in NK cells. As circadian and exogenous melatonin increase NK cell cytotoxicity, the presence of the endogenous melatonergic pathway may be of some importance not only to NK function and immune checkpoint regulation but also from the efflux of melatonin, which decreases tumor cell survival, proliferation, and metastasis, as well as decreasing immune checkpoint ligands, such as programmed cell ligand 1 (PD-L1). NK cell melatonergic pathway regulation may therefore have significant impacts not only on NK cell cytotoxicity but also on the intercellular interactions within tumors and other pathological microenvironments. As melatonin has anti-viral effects, the regulation of the NK cell melatonergic pathway can have wider impacts on how NK cells regulate viral infections, including in the course of viral-induced susceptibility to neurodegenerative conditions. Recent data indicate that the endogenous melatonergic pathway is regulated by interactions of signal transducer and activator of transcription (STAT)3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) dimer composition. As both STAT3 and NF-κB dimer composition modulate NK cells, their interaction in the modulation of the NK cell melatonergic pathway will be important to determine. This has significant future research and treatment implications, including improving the clinical efficacy of current treatment approaches such as immune checkpoint inhibition and chimeric antigen receptor (CAR) NK cell therapy, and may accelerate a means of preventing cancer.