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Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion
Open accessAbstract
A fresh look at glutamine targeting: Glutamine is essential for tumor growth and has long been an attractive therapeutic target for cancer researchers. Some attempts at blocking glutamine metabolism in cancer patients resulted in toxicity, prompting Leone et al. to develop an innovative approach to reduce general side effects. They designed a prodrug form (JHU083) of the glutamine antagonist 6-diazo-5-oxo- l -norleucine (DON), which is administered in an inert state but then preferentially activated by enzymes enriched in the tumor microenvironment. JHU083 simultaneously shut down glycolysis and oxidative phosphorylation in mouse cancer cells while enhancing T cell oxidative phosphorylation and anticancer immune responses. Science , this issue p. 1013
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“A recent study discovered a prodrug (JHU083) of the glutamine antagonist DON, which was designed to selectively become activated inside a tumor.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [200]
In the citing paper
“The researchers showed that blocking glutamine metabolism through JHU083 not only suppressed tumor cell metabolism but also mitigated the tumor microenvironment, which is hostile to the immune response due to its hypoxic, acidic, and nutrient-depleted conditions, unleashing the natural antitumor T cell response.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [200]
In the citing paper
“They also confirmed that concurrent treatment with JHU083 and anti-PD-1 checkpoint inhibitor improved the antitumor effects compared with anti-PD-1 treatment alone, suggesting the presence of metabolic plasticity between cancer cells and effector T cells, which could be exploited as a metabolic checkpoint for cancer immunotherapy200.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [200]
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“recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting203, including an orally available analog with promising pre-clinical results in murine PDAC models204”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [203]
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“…simultaneously suppressing anti-tumour immunity — HIF-1 a induces glycolytic enzymes in tumour cells while reducing OXPHOS capacity in cytotoxic T cells via lactate-mediated MCT inhibition, and MYC-driven glutamine consumption creates amino acid deprivation zones impairing TCR signalling (24, 55).”
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Inducing an oxidized redox-balance improves anti-tumor CD8 + T cell functionPreprint
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Traditional therapies and their moderation
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Metadata
- Authors
- Leone, R. D., Zhao, L., Englert, J. M., Sun, I.-M., Oh, M.-H., Sun, I.-H., Arwood, M. L., Bettencourt, I. A., Patel, C. H., Wen, J., Tam, A., Blosser, R. L., Prchalova, E., Alt, J., Rais, R., Slusher, B. S., & Powell, J. D.
- Affiliations
- Johns Hopkins University (US)
- Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
- Corresponding author
- Powell, Jonathan D.
- ORCID
- Venue
- Science
- Published
- 2019-11-22
- Volume
- 366
- Issue
- 6468
- Pages
- 1013-1021
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7023461
- OpenAlex
- W2985764787
- Cited by
- 1,169
- References
- 57
- Citations by year
- 2026: 143 · 2025: 196 · 2024: 195 · 2023: 181 · 2022: 197 · 2021: 160 · 2020: 92 · 2019: 4
- FWCI
- 35.99
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH Office of the Director (R01CA226765, R01CA229451)
- The Bloomberg∼Kimmel Institute for Cancer Immunotherapy.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- glutamine antagonist, tumor immune evasion, tumor microenvironment, cancer metabolism, oxidative metabolism, glycolysis, tumor hypoxia, tumor acidosis, effector T cells, antitumor immunity, metabolic checkpoint, cancer immunotherapy
- MeSH terms
- Animals, Azo Compounds, Caproates, Citric Acid Cycle, Energy Metabolism, Female, Glucose, Glutamine, Immunologic Memory, Lymphocyte Activation, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Tumor Escape, Tumor Microenvironment
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