The transcription factor BCL11B drives NK cell cytotoxicity and antitumor activity.

Bcl11b is a zinc-finger transcription factor that is required for the differentiation of αβ T cells. A role for BCL11B in the regulation of human natural killer (NK) cell maturation has been inferred from patients with heterozygous mutations in BCL11B. However, mechanistic and functional studies are lacking due to the low efficiency of current transduction and transfection methods. Here, we developed a synthetic BCL11B mRNA with enhanced stability that could be transfected into primary NK cells at high frequencies. Introduction of BCL11B mRNA slowed NK cell proliferation while simultaneously driving maturation and acquisition of cytotoxic granule components. For in vitro and in vivo functional testing, we generated induced pluripotent stem cell (iPSC)-derived NK (iNK) cells with inducible BCL11B expression. These iNK cells mediated faster solid tumor cell killing and significantly better tumor control in vivo. Together, our findings support the notion that BCL11B is a key transcription factor in human NK cells and demonstrate that increased BCL11B expression can enhance NK cell immunotherapy.