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EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
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Abstract
Abstract Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFNγ+CD8+ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil–depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors. Significance: This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.
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“EZH2 inhibition with GSK126 reportedly favors MDSC expansion and immunosuppressive functions”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Huang et al., 2019
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IGF2-IGF1R signaling inhibition delays the growth of IGF2-high colorectal cancer by modulating MDSCs
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Chandramoorthy, H. C. K., Zwamel, A. H., Mohammed, A. N., Baldaniya, L. H., Mustafa, Y. F., Mohammed, J. S., Singh, R. P., Kalia, R., Arya, R., & Yasin, H. A. (2025) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-025-04742-3
“Furthermore, EZH2 inhibitors, such as GSK126, have been shown to reduce antitumor immunity in conjunction with the expansion of MDSCs, highlighting an additional challenge to successful therapy, as they aim to alleviate immune system responses (Huang et al. 2019).”
Huang, C., Yu, B., Qiu, W., Cheng, H. B., & Li, S. (2025) · Advanced Therapeutics · doi:10.1002/adtp.202500270
Wu, S.-Y., Xie, Z.-Y., Yan, L.-Y., Liu, X.-F., Zhang, Y., Wang, D.-A., Dong, J., & Sun, H.-T. (2022) · Figshare · doi:10.6084/m9.figshare.20003701
Wu, S.-Y., Xie, Z.-Y., Yan, L.-Y., Liu, X.-F., Zhang, Y., Wang, D.-A., Dong, J., & Sun, H.-T. (2022) · Figshare · doi:10.6084/m9.figshare.20003704
Li, T., Han, B., Wang, L., Sun, L., Cai, Y., Yu, M., Xiao, W., & Yang, H. (2024) · Figshare · doi:10.6084/m9.figshare.26669688
PRMT6-mediated EZH2 arginine methylation is critical for breast cancer development
Han, X., Zhang, M., Lu, C., HUI, X., Du, S., Yue, C., & Yu, Z. (2026) · Oncogenesis · doi:10.1038/s41389-026-00619-z
Histone methylation machinery in gliomas: From enzymatic mechanisms to inhibitor development
Wang, X. C., Liu, W., Sun, J., Wei, X., Wang, Z., & Zang, L. (2026) · Cancer Treatment and Research Communications · doi:10.1016/j.ctarc.2026.101283
Beyond oncogenesis: The emerging role of EZH2 in tumor microenvironment
Hamad, J., Tarabain, N. E., Soufan, F., Fayyad‐Kazan, M., Issa, N., & Fayyad‐Kazan, H. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2026.105454
Mačvanin, M., & Klisic, A. N. (2026) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-026-10820-5
“GSK126 showed promise in atherosclerotic treatment as a highly selective EZH2 histone methyltransferase inhibitor that has been used to reduce macrophage pro-inflammatory responses [ 178].”
Myeloid-derived suppressor cells in cancer: biology, regulatory networks and theranostic prospects
Deng, R., Bai, X., Yang, J., Ye, W., Liu, Q., Xing, Y., Yao, Y., He, X., Lü, A., & Liu, Y. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02998-6
Patel, N. G., Drakaki, A., Valummel, F., Moore, J. C., Basu, A., Hu, B., Dong, X., Zhao, P., Botman, M., Spector, E., et al. (2026) · Communications Biology · doi:10.1038/s42003-026-10975-6
Bai, Y., Chen, H., & Gu, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1909464
Metadata
- Authors
- Huang, S., Wang, Z., Zhou, J., Huang, J., Zhou, L., Luo, J., Wan, Y. Y., Long, H., & Zhu, B.
- Affiliations
- Army Medical University (CN)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Long, Haixia
- Zhu, Bo
- Venue
- Cancer Research
- Published
- 2019-04-15
- Volume
- 79
- Issue
- 8
- Pages
- 2009-2020
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2911341716
- Cited by
- 185
- References
- 43
- Citations by year
- 2026: 10 · 2025: 28 · 2024: 28 · 2023: 30 · 2022: 29 · 2021: 29 · 2020: 21 · 2019: 9
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Nature Science Foundation of China (81472648, 81802865, and 81620108023)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- EZH2, GSK126, EZH2 inhibitors, myeloid-derived suppressor cells, antitumor immunity, tumor immune microenvironment, CD4+ T cells, CD8+ T cells, interferon-gamma, Gr-1, hematopoietic progenitor cells, myeloid differentiation, epigenetic regulation, combination therapy
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Myeloid-Derived Suppressor Cells, Animals, Colonic Neoplasms, Female, Humans, Indoles, Mice, Inbred C57BL, Mice, Nude, Pyridones, Tumor Cells, Cultured, Apoptosis, CD8-Positive T-Lymphocytes, Carcinoma, Lewis Lung, Receptors, Chemokine, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Antibodies, Neutralizing
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