Harnessing Natural Killer Cells: From Neuroimmunology to Novel Therapies for Central Nervous System Diseases

ABSTRACT Natural killer (NK) cells are innate lymphocytes that defend the host by directly killing virus‐infected, stressed, and tumor cells. Their direct cytotoxic mechanisms include the release of cytotoxic granules, engagement of death receptor pathways, and mediation of antibody‐dependent cellular cytotoxicity (ADCC). They can also eliminate targets indirectly via the secretion of proinflammatory cytokines. Importantly, recent studies show NK cells help limit autoimmunity by targeting autoreactive immune cells, highlighting their broader role in maintaining tissue homeostasis, including within the immune‐privileged central nervous system (CNS). Both preclinical and clinical studies support the therapeutic potential of NK cell‐based immunotherapies for neuroinflammatory, neurodegenerative, and neuro‐oncologic diseases. A key challenge remains achieving sufficient specificity and efficacy within the CNS, which necessitates a more profound understanding of NK cell biology in the unique brain microenvironment. This review summarizes the fundamental biology of NK cells and their roles in CNS pathologies, with a focus on their interactions with the CNS niche. We also discuss recent advances, such as immune‐engager strategies and adoptive NK cell therapies, aiming to provide insights to guide future therapeutic development for CNS disorders.