ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicEpigenetic Modulation in CancerView all 5 articles
DOT1L Promotes Immune Evasion in Lung Adenocarcinoma through H3K79me2-Mediated Epigenetic Activation of Immune Checkpoints
Provisionally accepted
- Guangzhou University of Chinese Medicine, Guangzhou, China
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The histone methyltransferase DOT1L, the sole enzyme catalyzing H3K79 methylation, is increasingly implicated in cancer progression, yet its role in shaping the tumor immune microenvironment (TME) remains unclear. Here, we demonstrate that DOT1L orchestrates immune evasion in lung adenocarcinoma (LUAD) through epigenetic activation of multiple immune checkpoints. Integrative analysis of TCGA and single-cell RNA-seq data revealed that high DOT1L expression correlates with poor prognosis, diminished cytotoxic immune-cell infiltration, and upregulation of inhibitory checkpoints (PD-L1, PD-1, LAG3, CD276, etc). Mechanistically, ChIP-seq identified DOT1L-mediated H3K79me2 enrichment at promoters of JAK1/STAT3 genes, and some immune checkpoints, including LAG3, CD276, etc. Pharmacological DOT1L inhibition (SGC0946) suppressed the JAK1/STAT3/PD-L1 axis, reduced PD-1+ T cells in a vitro immune microenvironment. In vivo, SGC0946 attenuated lung metastasis, improved survival, and remodeled the TME by downregulating PD-L1, LAG3, and CD276 expression, reduced PD-1+ T cells subsets, and along side with enhanced TNF-α, IFN-γ production. Clinical LUAD specimens further validated the correlation between DOT1L expression, STAT3 activation, and checkpoint upregulation, particularly in metastatic disease. Our findings identify DOT1L as an epigenetic linchpin of immune suppression.
Keywords: DOT1l, H3K79 methylation, Immune Evasion, Lung Adenocarcinoma, STAT3/PD-L1 axis
Received: 06 Oct 2025; Accepted: 23 Jan 2026.
Copyright: © 2026 Rao, Qi, Chen, Wang, Chai and Lin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xiwu Rao
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