Mitochondrial transfer enhances the metabolic fitness and antitumor activity of primary NK cells

Natural killer (NK) cell therapy has emerged as a promising approach for cancer treatment. However, its efficacy is often limited by metabolic dysfunction, poor persistence, and reduced activity within the tumor microenvironment. Here, we investigated whether mitochondrial transfer could improve the metabolic fitness and antitumor activity of peripheral blood-derived primary NK cells. Using a simple centrifugation-based approach, mitochondria isolated from NK cells or umbilical cord-derived mesenchymal stem cells (UC-MSCs) were transferred into primary NK cells. Mitochondrial transfer significantly enhanced oxidative phosphorylation, glycolysis, and ATP production, leading to improved cytokine secretion and cytotoxicity against both hematologic and solid tumor targets. In xenograft models, mitochondrial transfer significantly suppressed tumor growth, with UC-MSCs-derived mitochondria producing the greatest therapeutic benefit. Proteomic analysis further revealed enrichment of pathways associated with immune activation, cellular migration, and cytoskeletal remodeling. Collectively, these findings demonstrate that mitochondrial transfer enhances NK-cell metabolic fitness and antitumor activity, highlighting its potential as a practical non-genetic strategy for improving NK cell-based cancer immunotherapy.