Regulatable C-X-C chemokine receptor type 4 in iPSC-derived NK cells improves bone marrow chemotaxis and targeting resident tumor

iPSC-derived natural killer cells (iNKs) have emerged as a promising cellular therapy, especially for the refractory or relapsed acute myeloid leukemia (R/R AML) patients, but limited research focused on the chemotaxis of iNKs. Here we demonstrate that C-X-C chemokine receptor type 4 (CXCR4) is significantly reduced in iNKs, resulting in impaired bone marrow (BM) infiltration, which cannot be rescued by constitutively expressed CXCR4 in iPSC due to CXCR4-induced differentiation failure. To address this, we developed a strategy to allow specific expression of CXCR4 during the iNK maturation stage without compromising the final iNK yield and function. The engineered iNKs exhibited enhanced BM infiltration, resulting in improved therapeutic effects in AML murine models. This, brought attention to iNK chemotaxis, provided a meaningful strategy by incorporating well-designed gene editing with stem cells for cell product development, and obtained improved effective NK cells for AML therapy.