CAR-NK cell therapy in acute myeloid leukemia: safer, smarter, and moving toward clinical translation

Acute myeloid leukemia (AML) remains a highly lethal hematologic malignancy with limited durable treatment options and poor long-term survival. Allogeneic stem cell transplantation provides a curative approach for select patients, but outcomes are constrained by relapse and transplant-related morbidity. Chimeric antigen receptor (CAR) T-cell therapy, transformative in several lymphoid cancers, has shown limited efficacy in AML due to disease heterogeneity, antigen overlap with normal hematopoiesis, and treatment-related toxicities such as cytokine release syndrome and neurotoxicity. Natural killer (NK) cells offer an alternative cellular platform with intrinsic antitumor properties and a favorable safety profile. CAR-engineered NK (CAR-NK) cells combine the innate ability of NK cells to recognize malignant cells with the antigen specificity of CARs, offering targeted cytotoxicity while minimizing the risks of graft-versus-host disease and severe cytokine-driven toxicities. The use of allogeneic NK sources, including peripheral blood, umbilical cord blood, induced pluripotent stem cells, and NK cell lines, further supports the development of scalable “off-the-shelf” therapies. In this review, we summarize recent advances in CAR-NK therapy for AML. We discuss NK cell biology and CAR-NK design, evaluate emerging clinical trial data, and highlight key considerations for therapeutic development, including target antigen selection, NK cell sources, and engineering strategies to enhance persistence and function. Finally, we explore combination approaches and adjuvant agents that may overcome disease heterogeneity and immune evasion. Together, these insights underscore the potential of CAR-NK cells as a safer and more versatile next-generation immunotherapy in AML.