Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity

Nat Commun. 2022 Nov 2;13(1):6578. doi: 10.1038/s41467-022-34253-1.


Enhancer deregulation is a well-established pro-tumorigenic mechanism but whether it plays a regulatory role in tumor immunity is largely unknown. Here, we demonstrate that tumor cell ablation of mixed-lineage leukemia 3 and 4 (MLL3 and MLL4, also known as KMT2C and KMT2D, respectively), two enhancer-associated histone H3 lysine 4 (H3K4) mono-methyltransferases, increases tumor immunogenicity and promotes anti-tumor T cell response. Mechanistically, MLL4 ablation attenuates the expression of RNA-induced silencing complex (RISC) and DNA methyltransferases through decommissioning enhancers/super-enhancers, which consequently lead to transcriptional reactivation of the double-stranded RNA (dsRNA)-interferon response and gasdermin D (GSDMD)-mediated pyroptosis, respectively. More importantly, we reveal that both the dsRNA-interferon signaling and GSDMD-mediated pyroptosis are of critical importance to the increased anti-tumor immunity and improved immunotherapeutic efficacy in MLL4-ablated tumors. Thus, our findings establish tumor cell enhancers as an additional layer of immune evasion mechanisms and suggest the potential of targeting enhancers or their upstream and/or downstream molecular pathways to overcome immunotherapeutic resistance in cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enhancer Elements, Genetic
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Histones / metabolism
  • Humans
  • Interferons / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Neoplasms* / therapy
  • Phosphate-Binding Proteins / metabolism
  • Pyroptosis
  • RNA, Double-Stranded


  • Histone-Lysine N-Methyltransferase
  • Histones
  • RNA, Double-Stranded
  • Interferons
  • GSDMD protein, human
  • Phosphate-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • MLL4 protein, human