From innate power to intelligent design: The evolution of NK cell-based cancer immunotherapy

Natural killer (NK) cells have emerged as a promising platform for cancer immunotherapy due to their intrinsic cytotoxicity, lack of antigen restriction, and minimal risk of graft-versus-host disease, enabling the development of safe and scalable "off-the-shelf" therapies. However, their clinical efficacy, particularly in solid tumors, remains limited by poor in vivo persistence, inadequate tumor infiltration, and suppression by the immunosuppressive tumor microenvironment (TME). This review highlights the recent advances in genetic engineering strategies to enhance NK cell antitumor function. We discuss the optimization of chimeric antigen receptors (CARs) specifically for NK cells, the integration of immune checkpoint resistance, metabolic reprogramming, and the incorporation of cytokine support to improve survival and potency. In parallel, we explore combination strategies that synergize with NK cells, including monoclonal antibodies, oncolytic viruses, vaccines, and adoptive immune cell therapy. Additionally, we examine innovative platforms such as nanoparticle delivery systems and NK cell-derived exosomes to further enhance therapeutic outcomes. By systematically addressing the intrinsic and extrinsic limitations of NK cells through genetic precision and combinatorial immunomodulation, NK-based therapies are poised to transition from supportive to frontline modalities in cancer treatment. This review provides a comprehensive roadmap for the next generation of NK cell therapies with broad translational potential.