Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity PMID: 38991060

ADC Targets in Oncology

2026-04-10

Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

Science. 2024 Jul 12;385(6705):eadl6173. doi: 10.1126/science.adl6173.

Meng-Ju Wu ^# ¹ ² ³ ⁴ , Hiroshi Kondo ^# ¹ ² ³ ⁴ , Ashwin V Kammula ^# ¹ ³ ⁴ , Lei Shi ¹ ² ³ ⁴ , Yi Xiao ⁵ , Sofiene Dhiab ¹ ² ³ ⁴ , Qin Xu ¹ ² ³ ⁴ , Chloe J Slater ¹ ² ³ ⁶ ⁷ , Omar I Avila ¹ ³ ⁴ , Joshua Merritt ¹ ² ³ ⁴ , Hiroyuki Kato ¹ ² ³ ⁴ , Prabhat Kattel ¹ ² ³ ⁴ , Jonathan Sussman ⁸ ⁹ , Ilaria Gritti ¹ ² ³ ⁴ , Jason Eccleston ⁸ , Yi Sun ¹ , Hyo Min Cho ¹ ² ³ ⁴ , Kira Olander ⁴ , Takeshi Katsuda ⁸ , Diana D Shi ⁵ ¹⁰ , Milan R Savani ⁵ ¹¹ , Bailey C Smith ⁵ , James M Cleary , Raul Mostoslavsky ¹ ² ³ ⁴ , Vindhya Vijay ¹ ² ³ ⁴ , Yosuke Kitagawa ¹² , Hiroaki Wakimoto ¹² , Russell W Jenkins ¹ ³ ⁴ ¹³ , Kathleen B Yates ¹ ³ ⁴ , Jihye Paik ¹⁴ , Ania Tassinari ⁷ , Duygu Hatice Saatcioglu ⁷ , Adriana E Tron ⁷ , Wilhelm Haas ¹ ³ , Daniel Cahill ¹² , Samuel K McBrayer ⁵ ¹⁵ , Robert T Manguso ¹ ³ ⁴ , Nabeel Bardeesy ¹ ² ³ ⁴

Affiliations

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

Abstract

Isocitrate dehydrogenase 1 (IDH1) 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 IDH1-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. IDH1-mutant solid tumors show selective hypermethylation and silencing of the cytoplasmic double-stranded DNA (dsDNA) sensor CGAS, compromising innate immune signaling. mIDH1 inhibition restores DNA demethylation, derepressing CGAS 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.