Transcription factor Zhx2 restricts NK cell maturation and suppresses their antitumor immunity

The maturation and functional competence of natural killer (NK) cells is a tightly controlled process that relies on transcription factors (TFs). Here, we identify transcriptional repressor zinc fingers and homeoboxes 2 (Zhx2) as a novel regulator that restricts NK cell maturation and function. Mice with Zhx2 conditional deletion in NK cells (Zhx2(Delta/Delta)) showed accumulation of matured NK cells. Loss of Zhx2 enhanced NK cell survival and NK cell response to IL-15. Transcriptomic analysis revealed Zeb2, a key TF in NK cell terminal maturation, as a direct downstream target of Zhx2. Therapeutically, transfer of Zhx2-deficient NK cells resulted in inhibition of tumor growth and metastasis in different murine models. Our findings collectively unmask a previously unrecognized role of Zhx2 as a novel negative regulator in NK cell maturation and highlight its therapeutic potential as a promising strategy to enhance NK cell-mediated tumor surveillance.

Automated summary

The study identifies Zhx2 as a novel negative regulator that restricts NK cell maturation and function, with its loss enhancing NK cell survival and response to IL-15. Zhx2 deficiency in NK cells inhibits tumor growth and metastasis, highlighting its therapeutic potential for enhancing NK cell-mediated tumor surveillance.