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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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“It has recently been shown that combining glutamine antagonist and anti-PD-1 immunotherapydramatically improves antitumoreffects compared with anti-PD-1 therapy alone (69), revealing the bidirectional effect of glutamine deprivation with increasingOXPHOS and cell activity of CD8 T cells and decreasing the glycolysis i…”
BackgroundThe Role of Glutamine and Glutaminase in Pulmonary Hypertension
Wang, S., Yan, Y., Xu, W., Gong, S., Zhong, X.-J., An, Q.-Y., Zhao, Y., Liu, J., Wang, L., Yuan, P., et al. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.838657 · Cited by 25
“found that JHU-083 can not only inhibit the metabolism of glucose and glutamine in tumor cells, but also reverse the tumor microenvironment and maintain NADPH/NAD + homeostasis (114).”
BackgroundXu, Y., Xia, Z., Sun, X., Wei, B., Fu, Y., Shi, D., & Zhu, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1111319 · Cited by 26
“Moreover, blocking glutamine can induce different metabolic processes to overcome the immune escape of tumors and enhance the efficacy of immunotherapy (41, 42).”
BackgroundYing, H., Li, Z., Li, M.-P., & Liu, W. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1217669 · Cited by 29
“In the immune microenvironment, osteosarcoma cells influence the function of immune cells by regulating ammonia metabolic pathways (57, 58).”
BackgroundSun, X., Chen, H., Gao, R., Huang, Y., Qu, Y., Yang, H., Wei, X., Hu, S., Zhang, J., Wang, P., et al. (2023) · iScience · doi:10.1016/j.isci.2023.107790 · Cited by 26
Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy
Feng, B., Li, R., Li, W., & Tang, L. (2024) · Cell Systems · doi:10.1016/j.cels.2024.11.010 · Cited by 27
Lin, J., He, X.-L., Zhang, W., & Mo, C. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1584987 · Cited by 25
The Metabolism Symbiosis Between Pancreatic Cancer and Tumor Microenvironment
Li, Y., Zhang, J., Xu, J., & Liu, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.759376 · Cited by 24
“In contrast, the response of effector T cells to glutamine antagonism is to significantly upregulate oxidative metabolism and extend cell lifespan (70).”
BackgroundYing, L., Cheng, M., Lü, Y., Tao, Q., Chen, X., Shen, B., Xiong, F., Hu, Z., Wang, D., & Li, X. (2021) · Pathology & Oncology Research · doi:10.3389/pore.2021.1610075 · Cited by 25
“Glutamine blockade suppressed cancer cells but induced a long-lived, highly activated phenotype for effector T cells [22].”
BackgroundMonavarian, M., Elhaw, A. T., Tang, P. W., Javed, Z., Shonibare, Z., Scalise, C. B., Arend, R. C., Jolly, M. K., Sewell-Loftin, M. K., Hempel, N., et al. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.03.004 · Cited by 24
Yang, Y., Chen, L., Zheng, B., & Zhou, S. (2022) · Oncogene · doi:10.1038/s41388-022-02562-w · Cited by 27
“Activation-mediated cMyc expression is controlled by mTOR signaling and glutamine availability [22, 23, 25].”
BackgroundYu, C., Wang, N., Chen, X., Jiang, Y., Luan, Y., Qin, W., & He, W. (2023) · Materials Today Bio · doi:10.1016/j.mtbio.2023.100577 · Cited by 24
Single cell metabolic imaging of tumor and immune cells in vivo in melanoma bearing mice
Heaton, A. R., Rehani, P. R., Hoefges, A., Lopez, A. F., Erbe, A. K., Sondel, P. M., & Skala, M. C. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1110503 · Cited by 23
Dietary Manipulation of Amino Acids for Cancer Therapy
Jiménez‐Alonso, J. J., & López‐Lázaro, M. (2023) · Nutrients · doi:10.3390/nu15132879 · Cited by 26
Filament formation drives catalysis by glutaminase enzymes important in cancer progression
Feng, S., Aplin, C., Nguyen, T. T., Milano, S. K., & Cerione, R. A. (2024) · Nature Communications · doi:10.1038/s41467-024-46351-3 · Cited by 24
Hu, N., Li, H., Tao, C., Xiao, T., & Rong, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115584 · Cited by 28
“It also increases CD36 expression, a FA transporter [35,36].”
BackgroundMetabolic adaptations in cancer progression
Peng‐Winkler, Y., & Fendt, S. (2025) · Physiological Reviews · doi:10.1152/physrev.00037.2024 · Cited by 25
Metabolites as signalling molecules in the tumour immune microenvironment
Mao, Y., Xia, W., & Jiang, P. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-025-01258-y · Cited by 30
Ma, K., Han, X.-X., Han, X., & Zhou, S. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.308075 · Cited by 24
“This could be considered a form of immunotherapy, with the ability to modify the microenvironment of the tumor (Altman et al., 2016; Pavlova and Thompson, 2016; Leone et al., 2019).”
BackgroundDirecting T-Cell Immune Responses for Cancer Vaccination and Immunotherapy
Smith, P. L., Piadel, K., & Dalgleish, A. G. (2021) · Vaccines · doi:10.3390/vaccines9121392 · Cited by 24
Regulation of intrinsic and extrinsic metabolic pathways in tumour‐associated macrophages
Davuluri, G. V. N., & Chan, C. (2022) · FEBS Journal · doi:10.1111/febs.16465 · Cited by 25
Zhao, D., Zhang, J., Zhu, Y., He, C., Fei, W., Yue, N., Wang, C., & Wang, L. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.828612 · Cited by 23
“At the same time, the glutamine blockade can overcome tumor immune evasion (67); this is consistent with the results of pharmacological studies.”
ResultRegulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets
Chakraborty, S., Khamaru, P., & Bhattacharyya, A. (2022) · Cell Biology International · doi:10.1002/cbin.11867 · Cited by 24
Onohuean, H., Onohuean, F. E., Igbinoba, S. I., Ezeonwumelu, J. O. C., Agu, P. C., Ifie, J. E., Tusubira, D., & Aja, P. M. (2022) · Journal of Genetic Engineering and Biotechnology · doi:10.1186/s43141-022-00440-2 · Cited by 23
“In the current study, we suggest that the inhibition of the amino acids in the binding pockets by the MWL bioactive can lead to reduced tumor vascularity, increased tumor cell mortality, decreased cell proliferation, and poor tumor invasion [81, 82].”
BackgroundNguyen, T. T., Katt, W. P., & Cerione, R. A. (2022) · Future Drug Discovery · doi:10.4155/fdd-2022-0011 · Cited by 23
“In fact, inhibition of the PD-1/PD-L1 axis shows synergistic effects when combined with inhibitors of glutamine metabolism in restoring the immune response by T cells on patient-derived melanoma, as well as in a colon carcinoma model, and in clear cell ovarian carcinoma [3,97,98].”
BackgroundZhao, X., Li, K., Chen, M., & Liu, L. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114601 · Cited by 23
Role and therapeutic targeting of glutamine metabolism in non‑small cell lung cancer (Review)
Zhou, L., Zhang, Q., Zhu, Q., Zhan, Y., Li, Y., & Huang, X. (2023) · Oncology Letters · doi:10.3892/ol.2023.13745 · Cited by 23
“Results of glutamine antagonist experiments revealed the previously unknown difference in metabolic plasticity between cancer cells and effector T cells, which can be used as a ‘metabolic checkpoint’ for tumor immunotherapy (65).”
InfluentialAntitumor T‐cell function requires CPEB4‐mediated adaptation to chronic endoplasmic reticulum stress
Fernández‐Alfara, M., Sibilio, A., Martín, J., Uxó, E. T., Malumbres, M., Alcalde, V., Chanes, V., Cañellas-Socias, A., Palomo‐Ponce, S., Batlle, E., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022111494 · Cited by 22
Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer
Zhang, G.-Q., Chen, X., Ju, N.-T., Shen, C.-T., Qiu, Z.-L., Song, H.-J., & Luo, Q. (2024) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02294-y · Cited by 22
“Similarly, JHU-083 administration caused a marked increase in infiltrating CD8 + T cells; the cells were highly proliferative, robustly activated, less exhausted, and exhibited a less anergic phenotype [20, 23].”
BackgroundAllevato, M. M., Trinh, S., Koshizuka, K., Nachmanson, D., Nguyen, T., Yokoyama, Y., Wu, X., Andres, A. M., Wang, Z., Watrous, J. D., et al. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217089 · Cited by 24
Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment
Vitorakis, N., Gargalionis, A. N., Papavassiliou, K. A., Adamopoulos, C., & Papavassiliou, A. G. (2024) · Cancers · doi:10.3390/cancers16162876 · Cited by 25
“Glutamine antagonists together with PD-1 inhibitors also seem to be tumoricidal due to improved nutrient availability and consequent function of CD8+ T cells [176].”
BackgroundMetabolic landscape of disseminated cancer dormancy
Drápela, S., Garcia, B. M., Gomes, A. P., & Correia, A. L. (2024) · Trends in cancer · doi:10.1016/j.trecan.2024.10.005 · Cited by 24
Metabolic mechanisms of immunotherapy resistance
Cabezón‐Gutiérrez, L., Palka-Kotlowska, M., Custodio‐Cabello, S., Chacón-Ovejero, B., & Pacheco-Barcía, V. (2025) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2025.1002297 · Cited by 26
Acute Myeloid Leukemia: Is It T Time?
Khoud, M. B., Ingegnere, T., Quesnel, B., Mitra, S., & Brinster, C. (2021) · Cancers · doi:10.3390/cancers13102385 · Cited by 24
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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