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