ArticleCancer research2021
Hypoxia-Driven Oncometabolite L-2HG Maintains Stemness-Differentiation Balance and Facilitates Immune Evasion in Pancreatic Cancer.
Article in Cancer research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 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
60 citing papers in PubMed, 1 synthesis or guideline pooled it, 76 citations in OpenAlex.
- LDH and glycolytic activity as predictors of immunotherapy response in gastric cancer: a systematic review and meta-analysis.Frontiers in immunology · 2025Pooled it
- Molecular mechanisms and therapeutic strategies: DNA methylation in pancreatic cancer.Cancer biology & therapy · 2026Review
- Mass Spectrometry in Chiral Analysis and Synthesis.Chirality · 2026Article
- Impact of mitochondrial reductive stress due to respiratory chain limitation on cancer via posttranslational modifications.Redox biology · 2026Review
- [Lactate induces gastric mucosal injury by promoting M1 polarization of macrophagesNan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- Metabolites as signalling molecules in the tumour immune microenvironment.Nature reviews. Immunology · 2026Review
- The crosstalk between epigenetics and metabolism in the malignant cell.Discover oncology · 2026Review
- Hypoxic Tumor Microenvironment Targeting: Opportunities and Challenges for Pancreatic Cancer Immunotherapy.International journal of molecular sciences · 2026Review
- Targeting Glycolytic Metabolism in Cancer Therapy: Current Approaches and Future Perspectives.Cells · 2026Review
- Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.Molecular cancer · 2026Review
- The moonlighting functions of glycolytic enzymes in tumorigenesis.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Targeting metabolic-epigenetic-immune axis in cancer: molecular mechanisms and therapeutic implications.Signal transduction and targeted therapy · 2026Review
- Tryptophan metabolism in tumor immune escape: mechanisms, cellular crosstalk, and therapeutic opportunities.Frontiers in immunology · 2026Review
- Clinical Application Progress of Artificial Intelligence in Pancreatic Cancer: From Diagnosis to Immunotherapy.Oncology research · 2026Review
- Peritoneal metastasis in pancreatic cancer: molecular mechanisms, microenvironmental remodeling, and emerging intraperitoneal interventions.Frontiers in molecular biosciences · 2026Review
- Aerobic glycolysis-driven lactate accumulation and acidic tumor microenvironment in hepatocellular carcinoma: a vicious cycle promoting tumor progression.Frontiers in pharmacology · 2026Review
- The lactate-lactylation axis in tumor radioresistance: metabolic, epigenetic, and immune mechanisms with emerging links to RNA regulation.Frontiers in immunology · 2026Review
- 2-Hydroxyglutarate in onco-pathway: a metabolic driver of proto-oncogene activation.Frontiers in oncology · 2026Review
- Tumor-stromal metabolic crosstalk in pancreatic cancer.Trends in cell biology · 2025Review
- TCA cycle-derived oncometabolites in cancer and the immune microenvironment.Journal of biomedical science · 2025Review
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 1 country.
Funding
Abstract
In pancreatic cancer, the robust fibroinflammatory stroma contributes to immune suppression and renders tumors hypoxic, altering intratumoral metabolic pathways and leading to poor survival. One metabolic enzyme activated during hypoxia is lactate dehydrogenase A (LDHA). As a result of its promiscuous activity under hypoxia, LDHA produces L-2 hydroxyglutarate (L-2HG), an epigenetic modifier, that regulates the tumor transcriptome. However, the role of L-2HG in remodeling the pancreatic tumor microenvironment is not known. Here we used mass spectrometry to detect L-2HG in serum samples from patients with pancreatic cancer, comprising tumor cells as well as stromal cells. Both hypoxic pancreatic tumors as well as serum from patients with pancreatic cancer accumulated L-2HG as a result of promiscuous activity of LDHA. This abnormally accumulated L-2HG led to H3 hypermethylation and altered gene expression, which regulated a critical balance between stemness and differentiation in pancreatic tumors. Secreted L-2HG inhibited T-cell proliferation and migration, suppressing antitumor immunity. In a syngeneic orthotopic model of pancreatic cancer, inhibition of LDH with GSK2837808A decreased L-2HG, induced tumor regression, and sensitized tumors to anti-PD1 therapy. In conclusion, hypoxia-mediated promiscuous activity of LDH produces L-2HG in pancreatic tumor cells, regulating the stemness-differentiation balance and contributing to immune evasion. Targeting LDH can be developed as a potential therapy to sensitize pancreatic tumors to checkpoint inhibitor therapy. SIGNIFICANCE: This study shows that promiscuous LDH activity produces L-2HG in pancreatic tumor and stromal cells, modulating tumor stemness and immune cell function and infiltration in the tumor microenvironment.
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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.