ArticleThe Journal of clinical investigation2020
Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 130 papers, 1 of them a synthesis that pooled it.
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Who cites it
130 citing papers in PubMed, 1 synthesis or guideline pooled it, 209 citations in OpenAlex.
- Immune checkpoint inhibition for pancreatic ductal adenocarcinoma: limitations and prospects: a systematic review.Cell communication and signaling : CCS · 2021Pooled it
- Maternal hyperglycemia-induced O-GlcNAcylation of CaMKIIδ promotes mtDNA release and cardiac remodeling in offspring.Nature communications · 2026Article
- Efficacy of LNP@2DG-DON liposomal nanoparticles in tumor inhibition and immune activation.Journal of translational medicine · 2026Article
- Decoding the Hexosamine Biosynthesis Pathway: Implications for Novel Therapeutic Strategies in Sarcoma.Journal of cellular physiology · 2026Review
- The hypoxic ECM and neutrophils in MIBC immunotherapy resistance.Nature reviews. Urology · 2026Review
- Metabolic plasticity in pancreatic ductal adenocarcinoma progression and response to treatment.Molecular cancer · 2026Review
- The extracellular matrix in inflammation and cancer.Molecular biomedicine · 2026Review
- VISTA drives pancreatic tumor progression through modulation of the tumor-associated macrophage polarity.Nature communications · 2026Article
- GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Pancreatic cancer: molecular pathogenesis and emerging therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Targeting Glutamine Metabolic Reprogramming in Pancreatic Cancer: Current Insights and Future Directions.Current cancer drug targets · 2026Review
- Glutamine: fructose-6-phosphate amidotransferase (GFAT) in the pathology of diseases: a review.Cell death discovery · 2025Review
- The tumour microenvironment in pancreatic cancer - new clinical challenges, but more opportunities.Nature reviews. Clinical oncology · 2025Review
- The pronounced cytotoxic effects of chimeric antigen receptor T cells targeting B7-H3 in organoids and liver xenografts derived from colorectal cancer patients.British journal of cancer · 2025Article
- Immune infiltration and stromal heterogeneity in pancreatic cancer: A prognostic model guiding immunotherapy response.Oncology letters · 2025Article
- Exploring the metabolic signaling network of GFPT in cancer.Cell death discovery · 2025Review
- The Landscape of Cancer Metabolism as a Therapeutic Target.Pathology international · 2025Review
- Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches.Signal transduction and targeted therapy · 2025Review
- O-GlcNAcylation with ubiquitination stabilizes METTL3 to promoting HMGB1 degradation to inhibit ferroptosis and enhance gemcitabine resistance in pancreatic cancer.Molecular medicine (Cambridge, Mass.) · 2025Article
- Immunogenic Cell Death and Metabolic Reprogramming in Cancer: Mechanisms, Synergies, and Innovative Therapeutic Strategies.Biomedicines · 2025Review
70 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 1 institution in 1 country.
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine [DON]). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.
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