[Development of memory-like CAR-NK cells with durable antitumor activity]

Chimeric antigen receptor (CAR)-natural killer (NK) cell therapy has attracted increasing attention in recent clinical studies as a promising alternative to CAR-T cell therapy. CAR-NK cells offer several advantages, including a markedly lower risk of severe cytokine release syndrome and neurotoxicity, as well as the feasibility of developing off-the-shelf products due to the minimal potential for graft-versus-host disease. However, NK cells constitute only a small fraction of peripheral blood and have a relatively short lifespan, raising concerns about the durability of therapeutic efficacy. Recent advances have highlighted that, as in T-cell biology, the acquisition of memory-like phenotypes is critical for sustaining NK-cell function. Strategies to enhance NK-cell persistence, such as cytokine-induced memory-like NK cells and cytokine-engineered NK cells, have progressed rapidly. In parallel, alternative cellular sources, including umbilical cord blood-derived and induced pluripotent stem cell (iPSC)-derived NK cells, are being actively developed, enabling standardized manufacturing and large-scale production of uniform off-the-shelf products. In this review, we summarize the latest developments in CAR-NK cell research and discuss how genetic modulation of NK-cell differentiation pathways may contribute to the establishment of next-generation CAR-NK cell therapies with improved durability and antitumor efficacy.