Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity

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 anti-tumor immunity. Here, we define a cell-autonomous mechanism of mIDH1-driven immune evasion. IDH1-mutant solid tumors show striking, selective hypermethylation and silencing of the cytoplasmic 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 activates cGAS, triggering viral mimicry and stimulating anti-tumor immunity. Thus, we demonstrate that mIDH1 epigenetically suppresses innate immunity and link endogenous reverse transcriptase activity to the mechanism of action of an FDA-appro..., Supplemental table for the analyses of transposable elements from mutant IDH1 cancer cell lines treated with mIDH1 inhibitor by two pipelines (TEtranscript and SQuIRE), , # Mutant IDH1 inhibition activates tumor immunity via endogenous reverse transcriptase and dsDNA sensing

[https://doi.org/10.5061/dryad.5mkkwh7db](https://doi.org/10.5061/dryad.5mkkwh7db)

Supplemental table for the analyses of transposable elements from mutant IDH1 cancer cell lines treated with mIDH1 inhibitor by two pipelines (TEtranscript and SQuIRE)

# Description of the data and file structure

Our new analysis demonstrates that mIDH1 ICC cells have low baseline levels of TE expression (comparable to normal liver). First, for a clear presentation of baseline TE levels, we now provide supplementary data tables with the TETranscripts family level quantification for mouse ICC (**Supplementary Data Table 2**), mouse glioma (**Supplementary Data Table 4**), human ICC (**Supplementary Data Table 6**), and human glioma (**Supplementary Data Table 8**). We used an additional approach for locus specific quantification of TEs using the SQuIRE algorithm. We also provide supplementary data t...