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. [Display omitted] •DOT1L maintains a core transcriptional program defining NK cell phenotype and function•DOT1L impairs NK cell to intILC1/ILC1 phenotype conversion independent of TGF-β•Conditional DOT1L knockout mice display decreased tumor control Sudholz et al. identify DOT1L as a key regulator of NK cell phenotype and function. DOT1L-deficient NK cells exhibit an enhanced intILC1/ILC1 phenotype, irrespective of TGF-β. Conditional DOT1L knockout mice display decreased tumor control. We conclude that DOT1L may support MEF2C expression, which allows optimal NK cell phenotype and function.