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(R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple \u03b1-ketoglutarate\u2013dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate\u2013mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell\u2013autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon \u03b3 (IFN\u03b3) expression and promotes TET2-dependent induction of IFN\u03b3 response genes in tumor cells. CD8+ T-cell depletion or tumor cell\u2013specific ablation of TET2 or IFN\u03b3 receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFN\u03b3\u2013TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFN\u03b3. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies.<\/jats:p>\n                    <jats:p>See related commentary by Zhu and Kwong, p. 604.<\/jats:p>\n                    <jats:p>This article is highlighted in the In This Issue feature, p. 587<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-21-1077","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:26:24Z","timestamp":1638275184000},"page":"812-835","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":154,"title":["Mutant IDH Inhibits IFN\u03b3\u2013TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma"],"prefix":"10.1158","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6847-7065","authenticated-orcid":false,"given":"Meng-Ju","family":"Wu","sequence":"first","affiliation":[{"name":"1Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"2Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1149-0474","authenticated-orcid":false,"given":"Lei","family":"Shi","sequence":"additional","affiliation":[{"name":"1Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts."},{"name":"2Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-2208","authenticated-orcid":false,"given":"Juan","family":"Dubrot","sequence":"additional","affiliation":[{"name":"2Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts."},{"name":"3Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Merritt","sequence":"additional","affiliation":[{"name":"1Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7886-7443","authenticated-orcid":false,"given":"Vindhya","family":"Vijay","sequence":"additional","affiliation":[{"name":"1Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3073-625X","authenticated-orcid":false,"given":"Ting-Yu","family":"Wei","sequence":"additional","affiliation":[{"name":"1Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2608-6020","authenticated-orcid":false,"given":"Emily","family":"Kessler","sequence":"additional","affiliation":[{"name":"2Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts."},{"name":"3Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, 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Pennsylvania."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Heikenw\u00e4lder","sequence":"additional","affiliation":[{"name":"7Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina R.","family":"Ferrone","sequence":"additional","affiliation":[{"name":"10Department of Surgery, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lipika","family":"Goyal","sequence":"additional","affiliation":[{"name":"1Cancer Center, Massachusetts General Hospital, Boston, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Nicolay","sequence":"additional","affiliation":[{"name":"8Agios Pharmaceuticals, Cambridge, 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