EconPapers    
Economics at your fingertips  
 

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

Junlong Jack Chi, Ping Xie, Mary Hongying Cheng, Yueming Zhu, Xin Cui, Joshua Watson, Lidan Zeng, Amad Uddin, Hoang Nguyen, Lei Li, Kelley Moremen, April Reedy, Megan Wyatt, Adam Marcus, Mingji Dai, Chrystal M. Paulos, Massimo Cristofanilli, William J. Gradishar, Shaying Zhao, Kevin Kalinsky, Mine-Chie Hung, Ivet Bahar (), Bin Zhang () and Yong Wan ()
Additional contact information
Junlong Jack Chi: Emory University School of Medicine
Ping Xie: University Feinberg School of Medicine
Mary Hongying Cheng: Stony Brook University
Yueming Zhu: Emory University School of Medicine
Xin Cui: Emory University School of Medicine
Joshua Watson: University of Georgia
Lidan Zeng: Emory University School of Medicine
Amad Uddin: Emory University School of Medicine
Hoang Nguyen: Stony Brook University
Lei Li: Georgia State University
Kelley Moremen: University of Georgia
April Reedy: Emory University School of Medicine
Megan Wyatt: Emory University School of Medicine
Adam Marcus: Emory University School of Medicine
Mingji Dai: Emory University School of Medicine
Chrystal M. Paulos: Emory University School of Medicine
Massimo Cristofanilli: Weill Cornell Medicine
William J. Gradishar: University Feinberg School of Medicine
Shaying Zhao: University of Georgia
Kevin Kalinsky: Emory University School of Medicine
Mine-Chie Hung: China Medical University
Ivet Bahar: Stony Brook University
Bin Zhang: University Feinberg School of Medicine
Yong Wan: Emory University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58524-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58524-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58524-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().

 
Page updated 2025-05-10
Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58524-9