MGAT1-Guided complex N-Glycans on CD73 regulate immune evasion in triple-negative breast cancer
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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> IFNγ-producing T cell response. Collectively, our findings uncover a strategy for targeting the immunosuppressive molecule CD73 by inhibiting MGAT1.
Authors
- April R. Reedy (ORCID: https://orcid.org/0000-0001-7484-1986)
- Mary Hongying Cheng (ORCID: https://orcid.org/0000-0001-5833-8221)
- Kelley W. Moremen (ORCID: https://orcid.org/0000-0003-1768-582X)
- Shaying Zhao (ORCID: https://orcid.org/0000-0001-5852-9570)
- Joshua Watson (ORCID: https://orcid.org/0009-0006-5455-8810)
- Mingji Dai (ORCID: https://orcid.org/0000-0001-7956-6426)
- Massimo Cristofanilli (ORCID: https://orcid.org/0000-0002-4194-7175)
- Lidan Zeng (ORCID: https://orcid.org/0000-0001-8445-7451)
- Chrystal Mary Paulos (ORCID: https://orcid.org/0000-0002-0784-2601)
- Kevin Kalinsky (ORCID: https://orcid.org/0000-0002-3113-7902)
- Megan M. Wyatt (ORCID: https://orcid.org/0000-0003-1316-260X)
- Adam I. Marcus (ORCID: https://orcid.org/0000-0003-0484-3569)
- Mien‐Chie Hung (ORCID: https://orcid.org/0000-0003-4317-4740)
- İvet Bahar (ORCID: https://orcid.org/0000-0001-9959-4176)
- William J. Gradishar (ORCID: https://orcid.org/0000-0002-2772-3140)
- Junlong Chi (ORCID: https://orcid.org/0000-0002-2650-8756)
- Bin Zhang (ORCID: https://orcid.org/0000-0002-6631-7647)
- Lei Li (ORCID: https://orcid.org/0000-0002-1146-0761)
- Yong Wan (ORCID: https://orcid.org/0000-0001-9358-9392)
- Ping Xie (ORCID: https://orcid.org/0000-0002-2203-6990)
- Yueming Zhu (ORCID: https://orcid.org/0000-0002-3101-6238)
- Hoang Nguyen (ORCID: https://orcid.org/0000-0002-0251-3147)
- Xin Cui (ORCID: https://orcid.org/0000-0002-4451-210X)
- Amad Uddin (ORCID: https://orcid.org/0000-0001-7655-0373)
Institutions
- Northwestern University (US)
- Asia University (TW)
- Emory University (US)
- University of Georgia (US)
- Georgia State University (US)
- China Medical University (TW)
- Cornell University (US)
- Stony Brook School (US)
- Weill Cornell Medicine (US)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
- Stony Brook University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1038/s41467-025-58524-9
- Citations
- 7
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 7.82
Funders
- National Cancer Institute