Inhibition of Ferroptosis Enhances Anticancer Effect of Magnetized-Natural Killer Cell Therapy

Natural killer (NK) cell therapy is a promising approach for cancer immunotherapy; however, its clinical efficacy is limited by the low migration and infiltration of NK cells into solid tumors. Therefore, we used cell magnetization technology to enhance NK accumulation at tumor sites by incubating NK cells with ferucarbotran, a superparamagnetic iron oxide nanoparticle. We observed that NK cells could be magnetized, but their viability and cytotoxic function were significantly reduced because of lipid peroxide accumulation. However, treatment with the ferroptosis inhibitor restored NK cell function by inhibiting lipid peroxide accumulation. Additionally, NK cell magnetization decreased the expression of key anti-ferroptosis proteins, suggesting that magnetization induced ferroptosis. Furthermore, in a murine B16F10 melanoma mouse model, magnetized NK cells and ferroptosis inhibitors were transferred to tumor-bearing mice, followed by the application of a neodymium magnet to the tumor site to guide NK cell accumulation. Immunohistochemical analysis confirmed increased NK cell accumulation in the tumor tissue, suggesting that magnetization improved NK cell delivery to the tumor. Magnetized NK cells with the ferroptosis inhibitor significantly suppressed tumor growth and prolonged survival. These findings indicate that combining cell magnetization technology with ferroptosis inhibitors enhances NK cell therapy by improving tumor infiltration while preserving the cytotoxic function. This novel approach may be a promising strategy for improving the efficacy of NK cell-based therapies, particularly for solid tumors.