Background <p>Natural killer (NK) cells are key effector lymphoid cells involved in both innate and adaptive immunity and are capable of clearing abnormally aggregated α-synuclein (αSyn). In preclinical Parkinson’s disease (PD) models, NK cell depletion worsens motor deficits and increases insoluble αSyn accumulation, suggesting a neuroprotective role. However, the therapeutic potential of NK cell transfer in modulating αSyn pathology and neurodegeneration remains unexplored.</p> Methods <p>To assess the efficacy of NK cell therapy, we administered biweekly systemic injections of untouched NK cells isolated from B6C3H donor mice into 2-month-old presymptomatic homozygous M83 transgenic mice injected with human αSyn preformed fibrils. Neurological function was assessed via clasping behavior and clinical scoring. αSyn pathology and dopaminergic neurodegeneration were evaluated via immunohistochemistry. CyTOF-based immune profiling and multiplex ELISA were performed to characterize central and peripheral immune responses.</p> Results <p>Adoptive NK cell transfers improved motor function and reduced αSyn pathology in a region- and dose-dependent manner, with significant reductions in phosphorylated-αSyn inclusions&#xa0;and tyrosine hydroxylase-positive neuronal loss in the substantia nigra. NK cell transfer modulated the CNS immune landscape by reducing CD11b⁺CD45^high and MHCII⁺ activated microglial, CD4⁺ T cells, and neutrophil infiltration, while promoting CD19⁺ B and CD8⁺ T cells. Similar immunomodulatory effects were observed in the periphery, including restoration of follicular B cells and reduced neutrophil frequencies. Mechanistically, αSyn exposure downregulated activating NK ligands and upregulated inhibitory receptor ligand mQa1b, along with p21 induction in microglia, suggesting a senescence-associated, immune-evasive phenotype that may contribute to reduced therapeutic efficacy at later disease stages.</p> Conclusions <p>Our study provides direct evidence of NK cells exerting neuroprotective and immunomodulatory effects in a preclinical model of synucleinopathy. These findings support NK cell transfer as a novel therapeutic strategy for PD and related neurodegenerative disorders.</p>