Abstract
BACKGROUND: Acute myeloid leukemia (AML) remains a significant challenge in hematologic oncology, with high relapse rates and limited treatment options. Natural killer (NK) cells, as key effectors of innate immunity, have shown strong anti-leukemic activity, making them promising candidates for immunotherapy. Despite increasing clinical interest, a comprehensive evaluation of NK cell-based therapies in AML is still needed. METHODS: This systematic review follows the PRISMA guidelines to analyze clinical trials evaluating NK cell therapy in AML, either as a standalone treatment or in combination with hematopoietic stem cell transplantation (HSCT). A literature search across five major databases identified relevant studies, with data extraction focusing on NK cell sources, isolation and expansion strategies, clinical efficacy, and safety outcomes. RESULTS: A total of 48 clinical trials were identified, including 27 trials specific to AML and 21 trials involving AML along with other hematologic malignancies. Peripheral blood (PB)-derived NK cells were the main source (82%), with purification methods mainly using CliniMACS-based CD3 depletion and CD56 selection. Short-term activation (≤ 24 h) and long-term expansion (> 7 days) were employed in 36% of studies each. In non-HSCT transplant settings, NK cell therapy achieved a complete remission (CR) rate of 37.1% and an event-free survival (EFS) of 71.3%, while post-HSCT overall survival (OS) reached 39.5%. Notably, graft-versus-host disease (GVHD) incidence stayed low, highlighting the favorable safety profile of NK cell therapy. CONCLUSION: NK cell-based therapy represents a promising and well-tolerated immunotherapeutic approach for AML. However, optimizing NK cell expansion, persistence, and clinical applications requires further investigation through large-scale, controlled trials. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-025-14837-y