ArticleJCI insight2023
Cancer-associated fibroblasts reuse cancer-derived lactate to maintain a fibrotic and immunosuppressive microenvironment in pancreatic cancer.
Article in JCI insight, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
90 citing papers in PubMed, 1 synthesis or guideline pooled it, 78 citations in OpenAlex.
- Research trends on lactate in cancer: a bibliometric analysis and comprehensive review (2015-2024).Frontiers in immunology · 2025Pooled it
- Metabolic reprogramming in cancer-associated fibroblasts: orchestrating the tumor immune microenvironment and response to immune checkpoint blockade.Experimental hematology & oncology · 2026Review
- Lactate as a Signaling Molecule in the Tumor Microenvironment: Implications for Cancer Progression.Biochemical genetics · 2026Review
- Metabolic heterogeneity and functional diversity of cancer-associated fibroblasts in gastric cancer (Review).Oncology letters · 2026Review
- Hepatic stellate cells promote structural and functional remodeling of three-dimensional hepatocellular carcinoma coculture spheroids.Molecular biology reports · 2026Article
- Detection of Pancreatic Cancer via Specific Metabolite Markers: A Metabolomics Approach.Health science reports · 2026Article
- The Cancer Cell Metabolic Reprogramming Remodels the Tumor Microenvironment: Molecular Mechanisms and Therapeutic Strategies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Lactate metabolism and protein lactylation in inflammatory and tumor microenvironments.Molecular biomedicine · 2026Review
- Microbiome and pancreatic ductal adenocarcinoma: mechanistic insights, microenvironmental interactions, and therapeutic implications.Molecular biology reports · 2026Review
- The Metabolic Rheostat Index Uncovers Pathway-Level Coordination, Immunosuppressive Microenvironment Remodeling, and Therapeutic Co-Vulnerabilities in Pancreatic Ductal Adenocarcinoma.Current issues in molecular biology · 2026Article
- Roles of V-domain Ig suppressor of T-cell activation-mediated immunoregulation in tumor immune escape (Review).Oncology letters · 2026Review
- The evolving landscape of the Warburg effect in gastric cancer: From molecular mechanisms to targeted therapy.Clinical and translational medicine · 2026Review
- Rewiring glucose metabolism in pancreatic cancer by natural compounds: implications for immune evasion and therapeutic targets.Molecular biology reports · 2026Review
- Advances in Gastric Cancer Research: Insights Into Carcinogenesis, the Tumor Microenvironment, Metastasis, and Factors Influencing Prognosis.Annals of gastroenterological surgery · 2026Review
- Pestivirus bovine viral diarrhea virus infection induces ROS-HIF-1a axis-driven glycolytic reprogramming, which increases viral replication by impairing RIG-I-dependent type I interferon response.Journal of virology · 2026Article
- Lactate and lactylation in hepatocellular carcinoma: A new frontier in metabolic-epigenetic interactions.Medical oncology (Northwood, London, England) · 2026Review
- Deconstructing cancer in 3D: models, mechanisms, and personalized solutions.Molecular cancer · 2026Review
- SHH drives gastric cancer-associated fibroblast activation via ACLY-dependent acetyl-CoA metabolism and histone acetylation.Discover oncology · 2026Article
- Targeting Lactate and Lactylation in Cancer Metabolism and Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- The metabolic plasticity of cancer stem cells: bidirectional crosstalk with organ-resident cells.Experimental & molecular medicine · 2026Review
30 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
26 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Glycolysis is highly enhanced in pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for patients with PDAC, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL-6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides insight regarding the crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.
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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.