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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JHU083, a prodrug of DON, is designed to selectively activate inside a tumor.
“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]
Blocking glutamine metabolism through JHU083 suppressed tumor cell metabolism and mitigated the tumor microenvironment, unleashing an antitumor T cell response.
“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]
Concurrent JHU083 and anti-PD-1 improved antitumor effects compared with anti-PD-1 alone, suggesting metabolic plasticity between cancer cells and effector T cells.
“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]
Recent advances have optimized DON as a pro-drug with pharmacokinetic properties that increase tumor targeting, including an orally available analog with promising preclinical results in murine PDAC models.
“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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“171 Notably, DON showed the ability to signi fi cantly inhibit the generation and recruitment of MDSCs and to reprogram M2-like TAMs into proin fl ammatory TAMs, which increased tumor antigen cross-presentation to T cells and enhanced the ef fi cacy of immune checkpoint blockade (ICB).”
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“Glutamine blockade with JHU-083 monotherapy could also enhance endogenous antitumor immunity by triggering tumor immune rejection and adaptive immune memory without additional immunotherapy (106).”
BackgroundInfluentialGlutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer
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“Glutamine antagonism in tumour-bearing mice exhibits forceful antitumor effects by down-regulating oxidative and glycolytic metabolism of malignant cells but dramatically promoting oxidative metabolism of effector T cells.(343) In mineral metabolism, Se replenishment has antioxidant and DNA repair effects to exert ant…”
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Background
- 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 · 2018: 1
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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