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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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In the citing paper
“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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Engineering metabolism to modulate immunity
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Yang, Y., Li, Z., Wang, Y., Gao, J., Meng, Y., Wang, S., Zhao, X., Tang, C., Yang, W., Li, Y., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00051-z · Cited by 18
“…that cancer metabolism not only plays a crucial role in sustaining the growth and survival of tumor cells but also contributes to the regulation of antitumor immune responses by regulating the release of metabolites and the expression of immune molecules (Leone et al, 2019; Xia et al, 2021).”
Metabolic heterogeneity in tumor microenvironment – A novel landmark for immunotherapy
Chen, C., Han, P., & Qing, Y. (2024) · Autoimmunity Reviews · doi:10.1016/j.autrev.2024.103579 · Cited by 17
Targeting glutamine metabolism crosstalk with tumor immune response
Dong, C., Zhao, Y., Han, Y., Li, M., & Wang, G. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189257 · Cited by 21
Lei, C., Chen, W., Wang, Y., Zhao, B., Liu, P., Kong, Z., Liu, D., Dai, C., Wang, Y., Wang, Y., et al. (2021) · Journal of Cancer · doi:10.7150/jca.53827 · Cited by 17
“Further studies proved that glutamate and fatty acids’ metabolic processes differed significantly in hepatocellular carcinoma cells [8] while blocking glutamate-induced divergent metabolic programs to overcome tumor immune evasion [9].”
BackgroundSun, H., Wang, Y., Jing, H.-Y., Yang, X., Shi, X., Zhang, J., Yu, Y.-X., Gao, L., Wang, X., Li, W., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.629856 · Cited by 17
Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer
Fan, C., Kam, S., & Ramadori, P. (2021) · Cancers · doi:10.3390/cancers13205250 · Cited by 17
CAR T Cell Therapy’s Potential for Pediatric Brain Tumors
Thomas, P., Galopin, N., Bonerandi, E., Clemenceau, B., Fougeray, S., & Birklé, S. (2021) · Cancers · doi:10.3390/cancers13215445 · Cited by 17
Ma, J., Fu, S., Tan, J., Han, Y., Chen, Y., Deng, X., Shen, H., Zeng, S., Peng, Y., & Cai, C. (2025) · Advanced Science · doi:10.1002/advs.202502714 · Cited by 17
Amino acids metabolism: a potential target for cancer treatment
Ren, S., Zhou, X., Wang, Z., & Yuan, K. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02523-3 · Cited by 19
“Since the synthesis and degradation of glutamine are catalyzed by glutamine synthetase (GS) and GLS, respectively [136], we will discuss the effect of GLS and GS on tumors and explore strategies for cancer.”
Yang, H., Wu, C.-Y., Powell, J. D., & Lu, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21114030 · Cited by 17
“Recently, the anti-tumor effects of glutamine blockade with the prodrug of DON, JHU-083, has been tested out in tumor-bearing mice [230].”
BackgroundSelf-citationNguyen, T. T., Ramachandran, S., Hill, M. J., & Cerione, R. A. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101564 · Cited by 16
“Additional small molecules targeting GAC are also being developed as potential anticancer drugs (20).”
BackgroundWang, W., Jin, W., & Li, X. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166528 · Cited by 16
Liu, D., Wang, Y., Li, X., Wang, Y., Zhang, Z., Wang, Z., & Zhang, X. (2023) · Amino Acids · doi:10.1007/s00726-023-03316-y · Cited by 17
“…associated suppression of tumorigenesis with 6-diazo-5-oxo-L-norleucine (DON) a potent GLN antagonist and its less potent pro-drug substitutes, i.e., ethyl 2-(2-amino-4-methylpentanamido)- DON), has been reported in in vitro and in vivo preclinical models (Lemberg et al. 2018; Leone and Zhao 2019).”
BackgroundA redox-responsive prodrug for tumor-targeted glutamine restriction
Prange, C. J., Sayed, N. Y. B., Feng, B., Goepfert, C., Ortiz, D., Hu, X., & Tang, L. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.02.031 · Cited by 16
Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation
Chen, C., & Zhang, J. (2024) · Cancers · doi:10.3390/cancers16061171 · Cited by 18
“Similar scenarios have been observed with other amino acids, including glutamine and asparagine [120–122], which can lead to immuno-suppression or activation in certain circumstances.”
ResultZhao, L., Guo, J., Xu, S., Duan, M., Liu, B., Zhao, H., Wang, Y., Liu, H., Yang, Z., Yuan, H., et al. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.04.016 · Cited by 18
“Further studies have confirmed that blocking Gln in tumor-bearing mice inhibits oxidative and glycolytic metabolism in cancer cells, thereby reducing hypoxia, acidosis and nutrient depletion and enhancing antitumor immune responses [89].”
Self-citationGlutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells
Yuan, Z., Yu, T., Wang, X., Meng, K., Wang, T., Wang, B., Xi, Y., Wang, C., Zeng, C., Hu, S., et al. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107643 · Cited by 16
Lin, X., Zhou, W., Liu, Z., Cao, W., & Lin, C. (2022) · Oral Diseases · doi:10.1111/odi.14411 · Cited by 16
Combinatorial Epigenetic and Immunotherapy in Breast Cancer Management: A Literature Review
Lee, Y.-T., Chuang, Y., & Chan, M. W. Y. (2020) · Epigenomes · doi:10.3390/epigenomes4040027 · Cited by 18
“Previous studies have found that epigenetic changes also control the homeostasis of immune cells and contribute to immunosuppressive phenotypes [51,52].”
BackgroundThe Complex Roles of Redox and Antioxidant Biology in CancerPreprint
Hayashi, M., Okazaki, K., Papgiannakopoulos, T., & Motohashi, H. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041546 · Cited by 16
Lactate signaling and immune suppression in tumors: mechanisms and therapeutic implications
Wang, X., Xiong, D., Cui, S., Duan, B., Ding, G., Huang, Y., & Wang, Q. (2026) · Cellular Oncology · doi:10.1007/s13402-026-01186-6 · Cited by 16
“Pathways involving adenosine, kyn-urenine, glutamine, and fatty acids intersect with hypoxia and glycolysis [7].”
InfluentialZhang, Q., & Li, W. (2022) · World Journal of Stem Cells · doi:10.4252/wjsc.v14.i4.267 · Cited by 16
Immunometabolic alterations in lupus: where do they come from and where do we go from there?
Ma, L., Roach, T., & Morel, L. M. (2022) · Current Opinion in Immunology · doi:10.1016/j.coi.2022.102245 · Cited by 15
Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers
Moss, D., McCann, C. K., & Kerr, E. M. (2022) · Science Signaling · doi:10.1126/scisignal.abj3490 · Cited by 16
Glutamine metabolism and radiosensitivity: Beyond the Warburg effect
Alden, R. S., Kamran, M. Z., Bashjawish, B., & Simone, B. A. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1070514 · Cited by 18
“JHU083 with concurrent anti-PD-1 therapy in a MC38 mice showed complete response rate of ≥90%, compared to no complete responses with anti-PD-1 monotherapy (13).”
BackgroundMethodResultInfluentialMicrobiota configuration determines nutritional immune optimization
Han, S., Stacy, A., Corral, D., Link, V. M., Siqueira, M. K. D., Chi, L., Teijeiro, A., Yong, D., Pérez‐Chaparro, P. J., Bouladoux, N. J., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2304905120 · Cited by 17
Zheng, M., Xu, H., Huang, Y., Sun, J., Zhang, H., Lv, Z., Liu, Z., Tang, Z., & Chen, X. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.11.054 · Cited by 15
Immune evasion: An imperative and consequence of MYC deregulation
Krenz, B., Lee, J., Kannan, T., & Eilers, M. (2024) · Molecular Oncology · doi:10.1002/1878-0261.13695 · Cited by 15
“Glutamine metabolism has profound effects not only on tumor cells but also on immune cell activation, proliferation, and differentiation [122 – 124].”
BackgroundSpiga, M., Martini, E., Maffia, M. C., Ciceri, F., Ruggiero, E., Potenza, A., & Bonini, C. (2024) · Seminars in Immunopathology · doi:10.1007/s00281-024-01011-y · Cited by 16
“Inhibition of glutamine metabolism resulted in reduced tumor growth [187] and acted, in turn, on the glycolytic metabolism of tumor cells, favoring oxidative phosphorylation and leading to activation of effector T cells [188].”
Li, D., Cao, D., Zhang, Y., Yu, X., Wu, Y., Jia, Z., Jiang, J., & Cao, X. (2025) · Scientific Reports · doi:10.1038/s41598-024-84916-w · Cited by 15
Guo, Y., Jiang, T., Liang, S., Wang, A., Li, J., Jia, Y., Li, Q., Yin, J., Bai, S., & Li, J. (2025) · Advanced Science · doi:10.1002/advs.202412507 · Cited by 15
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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