iPSC-derived NK cells engineered with CD226 effectively control acute myeloid leukemia.

CD226 plays a vital role in NK cell cytotoxicity, interacting with its ligands on tumor targets. Acute myeloid leukemia (AML) cells have developed mechanisms to escape NK cell cytotoxicity, including inducing downregulation of CD226 on NK cells. Induced pluripotent stem cell -derived NK (iPSC-NK) cells offer an important source of standardized off-the-shelf NK cell therapy to treat AML patients. In this study, we engineered iPSC-NK cells with CD226 to assess the ability of killing AML cells. iPSC-NK cells engineered with CD226 have a typical NK cell phenotype and demonstrate improved anti-AML activity and multiple cytokines releasing at low effector-to-target ratios. Transcriptomic analysis revealed upregulation of immune effector function pathways associated with cytotoxicity and immune activation in CD226-overexpression iPSC-NK cells. In an AML xenograft model, mice treated with CD226 overexpression iPSC-NK cells exhibited significantly reduced leukemia burden, prolonged survival, decreased systemic inflammation compared to those treated with Control iPSC-NK cells. Overall, our study provided evidence that iPSC derived-NK cells engineered with CD226 represent a promising candidate for off-the-shelf immunotherapy, particularly in AML and other CD226 ligand-expressing malignancies.