2. Academic Validation
  3. MGAT1-Guided complex N-Glycans on CD73 regulate immune evasion in triple-negative breast cancer

MGAT1-Guided complex N-Glycans on CD73 regulate immune evasion in triple-negative breast cancer

  • Nat Commun. 2025 Apr 15;16(1):3552. doi: 10.1038/s41467-025-58524-9.
Junlong Jack Chi # 1 2 3 4,  Ping Xie # 5,  Mary Hongying Cheng # 6,  Yueming Zhu 1 2,  Xin Cui 1 2,  Joshua Watson 7,  Lidan Zeng 1 2,  Amad Uddin 1 2,  Hoang Nguyen 6,  Lei Li 8,  Kelley Moremen 9,  April Reedy 10,  Megan Wyatt 2 11,  Adam Marcus 2 10,  Mingji Dai 2 12,  Chrystal M Paulos 2 11,  Massimo Cristofanilli 13,  William J Gradishar 5,  Shaying Zhao 7,  Kevin Kalinsky 2 10,  Mine-Chie Hung 14 15,  Ivet Bahar 16 17,  Bin Zhang 18,  Yong Wan 19 20 21
Affiliations

Affiliations

  • 1 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
  • 2 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
  • 3 DGP graduate program, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 4 Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, USA.
  • 5 Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern, University Feinberg School of Medicine, Chicago, IL, USA.
  • 6 Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY, USA.
  • 7 Department of Biochemistry and Molecular Biology and Institute of Bioinformatics, University of Georgia, Athens, USA.
  • 8 Department of Chemistry, Georgia State University, Atlanta, USA.
  • 9 Complex Carbohydrate Research Center, University of Georgia, Athens, USA.
  • 10 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
  • 11 Department of Surgery/Microbiology & Immunology, Emory University School of Medicine, Atlanta, GA, USA.
  • 12 Department of Chemistry, Emory University School of Medicine, Atlanta, GA, USA.
  • 13 Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 14 Graduate Institute of Biomedical Sciences, Institute of Biochemistry and Molecular Biology, Cancer Biology and Precision Therapeutics Center, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan.
  • 15 Department of Biotechnology, Asia University, Taichung, Taiwan.
  • 16 Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, NY, USA. bahar@laufercenter.org.
  • 17 Department of Biochemistry and Cell Biology, School of Medicine, Stony Brook University, Stony Brook, NY, USA. bahar@laufercenter.org.
  • 18 Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern, University Feinberg School of Medicine, Chicago, IL, USA. bin.zhang@northwestern.edu.
  • 19 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. yong.wan@emory.edu.
  • 20 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA. yong.wan@emory.edu.
  • 21 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. yong.wan@emory.edu.
  • # Contributed equally.
PMID: 40229283 DOI: 10.1038/s41467-025-58524-9
Abstract

Despite the widespread application of immunotherapy, treating immune-cold tumors remains a significant challenge in Cancer therapy. Using multiomic spatial analyses and experimental validation, we identify MGAT1, a Glycosyltransferase, as a pivotal factor governing tumor immune response. Overexpression of MGAT1 leads to immune evasion due to aberrant elevation of CD73 membrane translocation, which suppresses CD8+ T cell function, especially in immune-cold triple-negative breast Cancer (TNBC). Mechanistically, addition of N-acetylglucosamine to CD73 by MGAT1 enables the CD73 dimerization necessary for CD73 loading onto VAMP3, ensuring membrane fusion. We further show that THBS1 is an upstream etiological factor orchestrating the MGAT1-CD73-VAMP3-adenosine axis in suppressing CD8+ T cell antitumor activity. Spatial transcriptomic profiling reveals spatially resolved features of interacting malignant and immune cells pertaining to expression levels of MGAT1 and CD73. In preclinical models of TNBC, W-GTF01, an inhibitor specifically blocked the MGAT1-catalyzed CD73 glycosylation, sensitizing refractory tumors to anti-PD-L1 therapy via restoring capacity to elicit a CD8+ IFNγ-producing T cell response. Collectively, our findings uncover a strategy for targeting the immunosuppressive molecule CD73 by inhibiting MGAT1.

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