Cited by 576T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersMitochondrial Function and Pathology

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Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen

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Vardhana, Santosha A., Hwee, Madeline A., Berisa, Mirela, Wells, Daniel K., Yost, Kathryn E., King, Bryan, Smith, Melody, Herrera, Pamela S., Chang, Howard Y., Satpathy, Ansuman T., van den Brink, Marcel R. M., Cross, Justin R., Thompson, Craig B.·2020·Nature Immunology

DOI 10.1038/s41590-020-0725-2PMC PMC7442749

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Abstract

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity. Thompson and colleagues show that repetitive antigenic stimulation within the tumor environment triggers mitochondrial dysfunction by inhibiting oxidative phosphorylation, which leads to T cell exhaustion.

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Liberzon, A., Birger, C., Thorvaldsdóttir, H., Ghandi, M., Mesirov, J. P., & Tamayo, P. (2015) · Cell Systems · doi:10.1016/j.cels.2015.12.004 · Cited by 13,807
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Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., Kadel III, E. E., Koeppen, H., Astarita, J. L., Cubas, R., et al. (2018) · Nature · doi:10.1038/nature25501 · Cited by 5,400
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Granhøj, J. S., Jensen, A. W. P., Presti, M., Met, Ö., Svane, I. M., & Donia, M. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2064711 · Cited by 76
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Humblin, É., Korpas, I., Lu, J., Filipescu, D., van der Heide, V., Goldstein, S., Vaidya, A. B., Schanoski, A. S., Casati, B., Selvan, M. E., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.adg0878 · Cited by 72
Targeted Anti‐Tumor Immunotherapy Using Tumor Infiltrating Cells
Xie, Y., Xie, F., Zhang, L., Zhou, X., Huang, J., Wang, F., Jin, J., Zhang, L., Zeng, L., & Zhou, F. (2021) · Advanced Science · doi:10.1002/advs.202101672 · Cited by 72
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Lv, Y., Li, Z., Liu, S., Zhou, Z., Jinling, S., Ba, Y., Weng, S., Zuo, A., Xu, H. W., Luo, P., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02407-6 · Cited by 93
Metabolic regulation of the cancer-immunity cycle
Patterson, L. F. S., & Vardhana, S. A. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.09.002 · Cited by 73
Self-citation
Metabolic plasticity and regulation of T cell exhaustion
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Lucotti, S., Ogitani, Y., Kenific, C. M., Geri, J. B., Kim, Y. H., Gu, J., Balaji, U., Bojmar, L., Shaashua, L., Song, Y., et al. (2025) · Cell · doi:10.1016/j.cell.2025.01.025 · Cited by 76
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Lutz, V., Hellmund, V. M., Picard, F. S. R., Raifer, H., Ruckenbrod, T., Klein, M., Bopp, T., Savai, R., Duewell, P., Keber, C. U., et al. (2023) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-22-0398 · Cited by 74
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Wen, J., Zhang, X., Wong, C., Zhang, Y.-T., Pan, Y.-S., Zhou, Y., Cheung, A., Liu, Y.-L., Ji, F.-F., Kang, X., et al. (2024) · Gut · doi:10.1136/gutjnl-2023-331117 · Cited by 71
Stripenn detects architectural stripes from chromatin conformation data using computer vision
Yoon, S., Chandra, A., & Vahedi, G. (2022) · Nature Communications · doi:10.1038/s41467-022-29258-9 · Cited by 65
CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies
Huang, J., Huang, X., & Huang, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1019115 · Cited by 72
Balanced engagement of activating and inhibitory receptors mitigates human NK cell exhaustion
Myers, J. A., Schirm, D. K., Bendzick, L. E., Hopps, R., Selleck, C., Hinderlie, P., Felices, M., & Miller, J. S. (2022) · JCI Insight · doi:10.1172/jci.insight.150079 · Cited by 63
Succinate-loaded tumor cell–derived microparticles reprogram tumor-associated macrophage metabolism
Lu, S., Li, J., Li, Y., Liu, S., Liu, Y., Liang, Y., Zheng, X., Chen, Y., Deng, J., Zhang, H., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adr4458 · Cited by 70
Proteotoxic stress response drives T cell exhaustion and immune evasion
Wang, Y., Ma, A., Song, N.-J., Shannon, A. E., Amankwah, Y. S., Chen, X., Wu, W., Wang, Z., Saadey, A. A., Yousif, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09539-1 · Cited by 68
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Liu, J., Shen, H., Gu, W., Zheng, H., Wang, Y., Ma, G., & Du, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.960738 · Cited by 61
Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1
Mortezaee, K., & Majidpoor, J. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114824 · Cited by 63
Targeting metabolism to enhance immunotherapy within tumor microenvironment
Liang, X., Chen, X., Yan, Y., Cheng, A.-Y., Lin, J.-Y., Jiang, Y.-X., Chen, H., Jin, J., & Luan, X. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-024-01304-w · Cited by 69
NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis
Huang, B., Lyu, Z., Qian, Q., Chen, Y., Zhang, J., Li, B., Li, Y., Liang, J., Liu, Q., Li, Y., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.06.014 · Cited by 60
Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease
Docampo, M. D., da Silva, M. B., Lazrak, A., Nichols, K. B., Lieberman, S. R., Slingerland, A. E., Armijo, G. K., Shono, Y., Nguyen, C. L., Monette, S., et al. (2021) · Blood · doi:10.1182/blood.2021010719 · Cited by 60
Self-citation
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Zhou, Z., Wang, J., Wang, J., Yang, S., Wang, R., Zhang, G., Li, Z., Shi, R., Wang, Z., & Lu, Q. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02047-2 · Cited by 66
Cellular senescence in cancer: from mechanism paradoxes to precision therapeutics
Feng, T., Xie, F., Lee, L. M.-Y., Lin, Z., Tu, Y., Lyu, Y., Yu, P., Wu, J., Chen, B., Zhang, G., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02419-2 · Cited by 70
Overcoming resistance to anti-PD-L1 immunotherapy: mechanisms, combination strategies, and future directions
Mandal, K., Barik, G. K., & Santra, M. K. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02400-z · Cited by 69
Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors
Muliaditan, T., Halim, L., Whilding, L. M., Draper, B., Achkova, D., Kausar, F., Glover, M., Bechman, N., Arulappu, A., Sanchez, J., et al. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100457 · Cited by 59
Fueling CARs: metabolic strategies to enhance CAR T-cell therapy
der Vreken, A. V., Vanderkerken, K., Bruyne, E. D., Veirman, K. D., Breckpot, K., & Menu, E. (2024) · Experimental Hematology and Oncology · doi:10.1186/s40164-024-00535-1 · Cited by 61
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Ye, J., Lin, Y., Liao, Z., Gao, X., Lu, C. Y., Lu, L., Huang, J., Huang, X., Huang, S., Yu, H., et al. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00752-1 · Cited by 64
Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia
Nelson, M. A. M., McLaughlin, K., Hagen, J. T., Coalson, H. S., Schmidt, C. A., Kassai, M., Kew, K. A., McClung, J. M., Neufer, P. D., Brophy, P. M., et al. (2021) · eLife · doi:10.7554/elife.63104 · Cited by 60
Delivery of mRNA Encoding Interleukin-12 and a Stimulator of Interferon Genes Agonist Potentiates Antitumor Efficacy through Reversing T Cell Exhaustion
Wang, B., Tang, M., Chen, Q., Ho, W., Teng, Y., Xiong, X., Jia, Z., Li, X., Xu, X., & Zhang, X. (2024) · ACS Nano · doi:10.1021/acsnano.4c00063 · Cited by 60

Authors: Vardhana, S. A., Hwee, M. A., Berisa, M., Wells, D. K., Yost, K. E., King, B., Smith, M., Herrera, P. S., Chang, H. Y., Satpathy, A. T., van den Brink, M. R. M., Cross, J. R., & Thompson, C. B.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Parker Institute for Cancer Immunotherapy (US)
Stanford Medicine (US)
Howard Hughes Medical Institute (US)
Corresponding author: Thompson, Craig B.
ORCID: Vardhana, Santosha A.
Berisa, Mirela
Wells, Daniel K.
Yost, Kathryn E.
King, Bryan
Smith, Melody
Chang, Howard Y.
Satpathy, Ansuman T.
Cross, Justin R.
Thompson, Craig B.
Venue: Nature Immunology
Publisher: Springer Science and Business Media LLC
Published: 2020-07-13
Volume: 21
Issue: 9
Pages: 1022-1033
ISSN: 1529-2908 (ISSN-L)
1529-2916
DOI: 10.1038/s41590-020-0725-2
PMC: PMC7442749
OpenAlex: W3040911066
Semantic Scholar: 0e26544b84036d0da9a73a3a38337fc7b1573819
Cited by: 575
References: 67
Citations by year: 2026: 133 · 2025: 117 · 2024: 112 · 2023: 90 · 2022: 68 · 2021: 46 · 2020: 9
FWCI: 18.62
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Immunology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health (1r01hl147584-01a1)
National Heart, Lung, and Blood Institute (R01‐HL147584)
National Cancer Institute (K08CA237731, P30CA008748)
National Institute of Allergy and Infectious Diseases (R25AI140472)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords: T cell exhaustion, mitochondrial oxidative phosphorylation, T cell self-renewal, chronic antigenic stimulation, T cell proliferation, mitochondrial oxidative stress, antioxidant treatment, redox homeostasis, tumor-infiltrating T cells, antitumor immunity
MeSH terms: Cell Self Renewal, Adenosine Diphosphate, Animals, Antigens, Neoplasm, Antioxidants, Energy Metabolism, Immune Tolerance, Lymphocyte Activation, Melanoma, Experimental, Mice, Inbred C57BL, Mitochondria, Neoplasms, Oxidative Phosphorylation, Lymphocytes, Tumor-Infiltrating, Clonal Anergy, CD8-Positive T-Lymphocytes, Cell Proliferation, Mice

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Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen

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