DOT1L maintains NK cell phenotype and function for optimal tumor control.

Histone methyltransferases (HMTs) are crucial in gene regulation and function, yet their role in natural killer (NK) cell biology within the tumor microenvironment (TME) remains largely unknown. We demonstrate that the HMT DOT1L limits NK cell conversion to CD49a+ CD49b+ intILC1, a subset that can be observed in the TME in response to stimulation with transforming growth factor (TGF)-β and is correlated with impaired tumor control. Deleting Dot1l in NKp46-expressing cells reveals its pivotal role in maintaining NK cell phenotype and function. Loss of DOT1L skews NK cells toward intILC1s even in the absence of TGF-β. Transcriptionally, DOT1L-null NK cells closely resemble intILC1s and ILC1s, correlating with altered NK cell responses and impaired solid tumor control. These findings deepen our understanding of NK cell biology and could inform approaches to prevent NK cell conversion to intILC1s in adoptive NK cell therapies for cancer.