The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen
Open accessAbstract
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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“Even though both oxidative and ER stress have been shown to contribute to T cell dysfunction across different tumor types (44-51),”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [50]
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Metadata
- 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
- Venue
- Nature Immunology
- Published
- 2020-07-13
- Volume
- 21
- Issue
- 9
- Pages
- 1022-1033
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- 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
- 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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