%0 Journal Article
%T Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity.
%A Wu MJ
%A Kondo H
%A Kammula AV
%A Shi L
%A Xiao Y
%A Dhiab S
%A Xu Q
%A Slater CJ
%A Avila OI
%A Merritt J
%A Kato H
%A Kattel P
%A Sussman J
%A Gritti I
%A Eccleston J
%A Sun Y
%A Cho HM
%A Olander K
%A Katsuda T
%A Shi DD
%A Savani MR
%A Smith BC
%A Cleary JM
%A Mostoslavsky R
%A Vijay V
%A Kitagawa Y
%A Wakimoto H
%A Jenkins RW
%A Yates KB
%A Paik J
%A Tassinari A
%A Saatcioglu DH
%A Tron AE
%A Haas W
%A Cahill D
%A McBrayer SK
%A Manguso RT
%A Bardeesy N
%J Science
%V 385
%N 6705
%D 2024 Jul 12
%M 38991060
%F 63.714
%R 10.1126/science.adl6173
%X 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.