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.
摘要：
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）产生代谢产物（R）-2-羟基戊二酸，破坏表观遗传学和其他过程中涉及的酶。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。这里,我们定义了mIDH1驱动的免疫逃避的细胞自主机制。IDH1突变实体瘤显示选择性超甲基化和细胞质双链DNA（dsDNA）传感器CGAS的沉默，损害先天免疫信号。mIDH1抑制恢复DNA去甲基化，抑制CGAS和转座因子（TE）亚类。由TE-逆转录酶（TE-RT）产生的dsDNA激活cGAS，引发病毒模仿和刺激抗肿瘤免疫。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学药物的作用机制联系起来.
