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Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction
Open accessAbstract
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
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“short hairpin RNAs (shRNAs) targeting EZH2 compromise the ability of CD8 + CTLs to mount robust immune responses”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Zhao et al., 2016
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“correlating with a positive prognostic impact for tumor infiltration by EHZ2 + CD8 + cells in patients with ovarian cancer”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Zhao et al., 2016
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Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome
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Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
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Self-citationIntratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
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The polycomb group protein EZH2 is involved in progression of prostate cancer
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Self-citationThe Polycomb group protein EZH2 directly controls DNA methylation
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Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204
Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer
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Wu, Q., Zhang, Q., Yan, W., Sun, L., Cui, Y., Liu, B., Han, G., Zhang, F. Q., Pu, K., Zhang, M., et al. (2026) · Advanced Science · doi:10.1002/advs.76316
Self-citationCD8 + Tissue‐Resident Memory T Cells in Health and Disease
Ai, Y.-H., Xu, T., Lin, S., Xiao, M., Lin, Y.-X., Ma, H. Y., Liu, Y., Wang, Y., Yin, L., Huang, M., et al. (2026) · MedComm · doi:10.1002/mco2.70838
Self-citationBiltekin, E., & Özpolat, B. (2026) · Non-Coding RNA · doi:10.3390/ncrna12050034
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Yang, X.-F., Wang, Y.-D., You, H.-Y., Gao, J.-Y., Feng, Y.-K., Zhang, F., Zhang, Y., Zhang, B., Zhao, S.-J., & Gu, Y.-F. (2026) · Clinical and Translational Medicine · doi:10.1002/ctm2.70836
Self-citationMatteo, S. D., & Gnocchi, D. (2026) · Biology · doi:10.3390/biology15191790
Wang, M., Chen, J., 吴中华, Wang, Z., Zhong, Z., & Zhong, Y. (2026) · Biomarker Research · doi:10.1186/s40364-026-01011-0
Self-citationBai, Y., Chen, H., & Gu, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1909464
Metadata
- Authors
- Zhao, E., Maj, T., Kryczek, I., Li, W., Wu, K., Zhao, L., Wei, S., Crespo, J., Wan, S., Vatan, L., Szeliga, W., Shao, I., Wang, Y., Liu, Y., Varambally, S., Chinnaiyan, A. M., Welling, T. H., Marquez, V., Kotarski, J., Wang, H., Wang, Z., Zhang, Y., Liu, R., Wang, G., & Zou, W.
- Affiliations
- University of Michigan (US)
- Medical University of Lublin (PL)
- Wuhan Union Hospital (CN)
- Corresponding author
- Wang, Guobin
- Zou, Weiping
- ORCID
- Venue
- Nature Immunology
- Published
- 2015-11-02
- Volume
- 17
- Issue
- 1
- Pages
- 95-103
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC4684796
- OpenAlex
- W2202401513
- Cited by
- 405
- References
- 50
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 37 · 2023: 35 · 2022: 54 · 2021: 51 · 2020: 42 · 2019: 34 · 2018: 38 · 2017: 35 · 2016: 29 · 2015: 1
- FWCI
- 15.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL127351)
- National Cancer Institute (R01CA092562, CA099985, R01CA123088, R01CA152470, R01CA156685, R01CA172106, CA123088, 5P30 CA 46592, CA156685, R01CA171306, R01CA193136, CA171306, R01CA099985, R01CA190176, P30CA046592)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- tumor immune evasion, EZH2, microRNA, miR-101, miR-26a, glycolysis, glucose restriction, Notch signaling, H3K27me3, Numb, FBXW7, T cell apoptosis, ovarian cancer, antitumor immunity, CD8+ T cells
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Animals, Cell Separation, Female, Flow Cytometry, Fluorescent Antibody Technique, Glycolysis, Humans, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasms, Ovarian Neoplasms, T-Lymphocytes, Transfection, Immunoblotting, Gene Expression Regulation, Neoplastic, Tumor Escape, MicroRNAs, Tissue Array Analysis, Chromatin Immunoprecipitation, Real-Time Polymerase Chain Reaction, Polycomb Repressive Complex 2
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