Natural killer cell-derived extracellular vesicles reprogram cellular human immunity to enhance tumor cytotoxicity

Natural killer (NK) cells are part of the body's first line of defense that rapidly destroy stressed, infected, or cancerous cells. These immune cells release nanosized biological packages called extracellular vesicles (EVs), which transfer molecular signals between cells and influence immune function. Although NK cell-derived EVs (NK92-EVs) have shown the ability to directly kill cancer cells, how they shape the broader human immune response has remained unclear. Here, NK92-EVs were shown to reprogram cellular human immunity to enhance tumor cytotoxicity using single-cell transcriptomics and functional cytotoxicity assays. When human peripheral blood mononuclear cells (PBMCs) from healthy and cancer patients (who exhibit systemic dysregulation) were exposed to NK92-EVs, widespread shifts in gene activity occurred across key immune populations, notably CD8⁺ T cells and NK cells. These changes enhanced the cells' ability to recognize and eliminate tumor targets and were consistent across all donors. Functional depletion and enrichment experiments, together with transcriptomic profiling, provide direct evidence that NK92-EV-mediated immune reprogramming enhances NK cell-driven, MHC-I-independent tumor cytotoxicity, but not for CD4⁺ and CD8⁺ T cells. This work advances understanding of immune communication and highlights NK92-EVs as promising, cell-free candidates for the next generation of cancer immunotherapies that unite potency with clinical scalability.