What question did this study set out to answer?

The aim is to explore how EHMT2 regulates NK cell maturation and its potential as a therapeutic target in cancer immunotherapy.

July 26, 2026Open Access

Targeting EHMT2 enhances NK cell maturation and antitumor activity

MYMinghang YuCapital University XLXinhua LiuHangzhou Normal University WZWei ZhangNanjing University of Chinese Medicine

Key Points

The aim is to explore how EHMT2 regulates NK cell maturation and its potential as a therapeutic target in cancer immunotherapy.
Identified EHMT2's role through RNA-seq and CUT&Tag profiling in NK cells following cytokine activation.
Performed NK cell-specific deletion of Ehmt2 in mice and assessed maturation and effector functions.
Utilized pharmacological inhibition of EHMT2 in human NK cell models to evaluate effects on maturation and cytotoxicity.
EHMT2 deletion in mice leads to increased IFN-γ production and enhanced NK cell cytotoxicity.
Loss of EHMT2 correlates with reduced H3K9me2 levels and activation of NK cell differentiation programs.
Pharmacological inhibition of EHMT2 in human NK cells promotes terminal maturation and improves tumor cell killing.

Abstract

Abstract Natural killer (NK) cells are critical for both innate and adaptive immunity, and their effective regulation holds significant promise for tumor immunotherapy. The terminal maturation of NK cells is closely associated with enhanced effector functions, but the role of epigenetic mechanisms in this process remains incompletely understood. Here, we identify the histone methyltransferase EHMT2 as an epigenetic regulator that restrains NK cell maturation and function. EHMT2 expression is markedly downregulated upon cytokine activation in human NK cells and inversely correlated with effector gene expression across tissues and cancer types. NK cell-specific deletion of Ehmt2 in mice promotes terminal NK cell maturation, augmenting IFN-γ production and cytotoxicity both in vitro and in vivo. Integrated RNA-seq and H3K9me2 CUT&Tag profiling reveal that Ehmt2 loss reduces the repressive histone mark H3K9me2 and derepresses transcriptional programs associated with NK cell differentiation and cytotoxicity. Pharmacological inhibition of EHMT2 recapitulated these effects in both human umbilical cord blood (hUCB)-hematopoietic stem cell (HSC)-derived NK cells and peripheral blood NK cells, promoting terminal maturation and tumor cell killing. These findings define EHMT2-dependent H3K9me2 deposition as a key epigenetic barrier to NK cell effector programming and suggest that targeting EHMT2 may potentiate NK cell-based immunotherapies.

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