Natural Killer Cells Therapy: From in Vitro Amplification to Engineering Modification

In cancer treatment, traditional therapies are limited, and T-cell therapies are faced with challenges such as high costs and toxicity. As a mainstay of innate immunity, natural killer (NK) cells offer distinct advantages, including the ability to kill target cells without antigen sensitization, a low risk of graft-versus-host disease (GVHD), and the potential for "off-the-shelf" application. This review summarizes recent advancements in NK cell-based therapies, focusing on in vitro amplification strategies and genetic engineering modifications. Key findings include: cytokine and feeder layer co-culture systems have been shown to expand NK cells over 500-fold; CD19-targeted chimeric antigen receptor (CAR)-NK cells exhibit a 50%-70% response rate in B-cell lymphoma patients; CRISPR-mediated gene editing enhances cytotoxicity against solid tumors; nanoparticle-based delivery systems improve tumor infiltration of NK cells; and allogeneic NK cell therapy carries a near-zero GVHD risk. Notably, significant challenges persist, such as the immunosuppressive tumor microenvironment, poor in vivo persistence of NK cells, congenital functional defects, potential off-target effects of CAR-NK cells, and the lack of standardized production protocols. While NK cell therapy demonstrates substantial promise in cancer immunotherapy, overcoming these bottlenecks is essential for its broader clinical translation and application.