Abstract Natural killer cells defend against malignancies and viral infections through a tightly controlled program of differentiation and maturation. However, the transcriptional mechanisms guiding this process remain incompletely defined. Using paired single-cell multiomic profiling, we identify GFI1 as an epigenetic regulator of NK cell differentiation, coordinating EOMES and T-BET transcriptional balance to promote NK cell proliferation and the transition from immature to terminally differentiated NK cell states. GFI1 represses FOXO1 chromatin accessibility in mature NK cells, which normally limits NK cell proliferation and maturation. Co-deletion of both GFI1 and FOXO1 largely rescues NK cell differentiation, identifying a critical GFI1–FOXO1 axis required for protection against tumour metastasis. These findings position GFI1 as a key transcriptional node integrating NK cell differentiation, activation and effector programs.
Huang et al. (Wed,) studied this question.