ArticleCancer discovery2022
Mutant IDH Inhibits IFNγ-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
98 citing papers in PubMed, 1 synthesis or guideline pooled it, 136 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
- Clinical and translational study of ivosidenib plus nivolumab in advanced solid tumors harboring IDH1 mutations.The oncologist · 2025Trial
- Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.The oncologist · 2024Trial
- Cholangiocarcinoma:Unveiling the cold tumor microenvironment and strategies for immune rejuvenation.Oncogene · 2026Review
- Expression Of the Idh1 R132h Protein in Hepatopancreatobiliary Malignancies in A Single Center Population: Immunohistochemical Study.Iranian journal of pathology · 2026Article
- Circulating tumor DNA-based detection of molecular residual disease in isocitrate dehydrogenase-mutant cholangiocarcinoma for biomarker-guided therapy.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Review
- Regulation of immune checkpoint molecules in cancer immune evasion and therapy.Nature reviews. Cancer · 2026Review
- TET2 as a Context-Dependent Epigenetic Integrator in Clonal Hematopoiesis, Inflammation, Cancer, and Immunotherapy.Cell biochemistry and function · 2026Review
- Effectiveness and safety of PD-1/PD-L1 inhibitors plus lenvatinib with or without Gemox chemotherapy in advanced intrahepatic cholangiocarcinoma.BMC cancer · 2026Article
- Advances in Immunotherapy for Intrahepatic Cholangiocarcinoma.International journal of molecular sciences · 2026Review
- Cancer stem cell plasticity: mechanisms, immune microenvironment crosstalk, and therapeutic implications.Journal of hematology & oncology · 2026Review
- Role of the stromal and immune microenvironment in intrahepatic cholangiocarcinoma.JHEP reports : innovation in hepatology · 2026Review
- The Evolving Landscape of Immune Regulation and Immunotherapy in Cholangiocarcinoma and Biliary Tract Cancer.Cancers · 2026Review
- Loss of tumor-infiltrating lymphocytes and poor response to immunotherapy in IDH GOF mutant melanoma.JCI insight · 2026Article
- Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates.Nature chemistry · 2026Article
- Review
- Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma.Cell reports. Medicine · 2026Article
- Review
- How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration.Medical review (2021) · 2026Review
38 more citing papers are in PubMed but not listed here.
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Authors and funding
33 authors at 7 institutions in 2 countries.
Funding
Abstract
Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate-dependent 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-mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell-autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell-specific ablation of TET2 or IFNγ 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 IFNγ-TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. SIGNIFICANCE: 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 IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.