Natural Killer Cells: Dual Regulators and Therapeutic Targets in Multiple Sclerosis Immunopathogenesis

Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Natural killer cells participate in MS through context-dependent regulatory and cytotoxic functions, yet their precise contribution to disease remains incompletely defined. This review summarizes current knowledge on NK cell development, receptor-mediated activation and inhibition, and mechanisms shaping NK cell responses in the inflamed central nervous system. We examine evidence from experimental autoimmune encephalomyelitis and clinical studies describing how distinct NK subsets may exert protective or pathogenic effects depending on disease stage and microenvironment. Emerging strategies to modulate NK cell function, including cytokine-based stimulation, metabolic and epigenetic regulation, and engineered NK platforms, are also discussed. These approaches have been primarily developed in oncology, and their relevance to MS currently remains preclinical, with only early exploratory efforts reported in autoimmune contexts. Overall, we aim to provide a clear and updated assessment of NK cell biology in MS and to outline the opportunities and limitations of NK-targeted interventions. Further mechanistic and translational studies are required before NK-focused strategies can be reliably considered for therapeutic development in MS.