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.

中文翻译：

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突变型 IDH1 抑制诱导 dsDNA 感应激活肿瘤免疫


异柠檬酸脱氢酶 1 （IDH1） 是人类癌症中最常见的突变代谢基因。突变体 IDH1 （mIDH1） 产生癌代谢物 （R）-2-羟基戊二酸，破坏参与表观遗传学和其他过程的酶。IDH1 突变实体瘤的一个标志是 T 细胞排斥，而临床前模型中的 mIDH1 抑制可恢复抗肿瘤免疫。在这里，我们定义了 mIDH1 驱动的免疫逃避的细胞自主机制。IDH1 突变实体瘤显示细胞质双链 DNA （dsDNA） 传感器 CGAS 的选择性高甲基化和沉默，损害先天免疫信号传导。mIDH1 抑制可恢复 DNA 去甲基化，去抑制 CGAS 和转座因子 （TE） 亚类。TE 逆转录酶 （TE-RT） 产生的 dsDNA 激活 cGAS，触发病毒模拟并刺激抗肿瘤免疫。总之，我们证明 mIDH1 表观遗传学抑制先天免疫，并将内源性 RT 活性与美国食品和药物管理局批准的肿瘤药物的作用机制联系起来。