Dual function of DOT1L suppresses tumor cell-intrinsic immunogenicity in hepatocellular carcinoma

  • Oncogene. 2026 May;45(16):1484-1500. doi: 10.1038/s41388-026-03744-6.
Siyuan Xu  1 ,  Ruijie Gong  2 ,  Songchen Liu  1 ,  Jianhua Wang  1 ,  Yijie Shen  1 ,  Chuxuan Peng  1 ,  Qin Feng  1 ,  Min Luo  3 ,  Fei Lan  4 ,  Jia Fan  2 ,  Jiabin Cai  5  6 ,  Xianjiang Lan  7
Affiliations
  • 1. Department of Systems Biology for Medicine, School of Basic Medical Sciences, Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2. Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Medical Epigenetics and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 3. Institute of Pediatrics of Children's Hospital of Fudan University, the Shanghai Key Laboratory of Medical Epigenetics, the International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 4. Shanghai Key Laboratory of Medical Epigenetics, State International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 5. Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Institutes of Biomedical Sciences, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Key Laboratory of Medical Epigenetics and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
  • 6. Department of Liver Surgery, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China. [email protected].
  • 7. Department of Systems Biology for Medicine, School of Basic Medical Sciences, Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. [email protected].
PMID: 41912776 DOI: 10.1038/s41388-026-03744-6
Abstract

Immune checkpoint blockade (ICB) therapy for many cancers remains limited in patients' overall response rate. Discovery and development of more effective combinatorial approaches is urgent. Here, through CRISPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress tumor-intrinsic immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type I interferon (IFN) response, and meanwhile lowers ZEB1 levels to further unleash the expression of immune-related genes. In turn, we demonstrate that DOT1L loss or treatment with the clinical stage inhibitor EPZ-5676 sensitizes tumors to ICB with increased immune infiltration in mice. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mice. TCGA data analysis reveals an inverse correlation between DOT1L expression and IFN signatures across multiple Cancer types. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.

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