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Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Affiliations
  • 1Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston MA, USA.
  • 2Center for Regenerative Medicine, Massachusetts General Hospital, Boston MA, USA.
  • 3Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 4Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
  • 5Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6Universite Paris-Saclay, Institut Gustave Roussy, INSERM U1015, Villejuif, France.
  • 7Servier Pharmaceuticals LLC, Boston, MA, USA.
  • 8Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 9Graduate Group in Genomics and Computational Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 10Department of Radiation Oncology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA, USA.
  • 11Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 12Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 13Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • 14Department of Pathology and Laboratory Medicine, Sandra and Edward Meyer Cancer Center, Weill Medical College of Cornell University, New York, NY, USA.
  • 15Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Published on:

July 11, 2024

Abstract

() is the most commonly mutated metabolic gene across human cancers. Mutant IDH1 (mIDH1) generates the oncometabolite (R)-2-hydroxyglutarate, disrupting enzymes involved in epigenetics and other processes. A hallmark of -mutant solid tumors is T cell exclusion, whereas mIDH1 inhibition in preclinical models restores antitumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. -mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor , compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing and transposable element (TE) subclasses. dsDNA produced by TE-reverse transcriptase (TE-RT) activates cGAS, triggering viral mimicry and stimulating antitumor immunity. In summary, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous RT activity to the mechanism of action of a US Food and Drug Administration-approved oncology drug.

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