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-approved oncology drug.