N-deglycosylation targeting chimera (DGlyTAC): a strategy for immune checkpoint proteins inactivation by specifically removing N-glycan

  • Signal Transduct Target Ther. 2025 Apr 28;10(1):139. doi: 10.1038/s41392-025-02219-6.
Li Li  1 ,  Jiajia Wu  2 ,  Weiqian Cao  3 ,  Wei Zhang  3 ,  Qi Wu  1 ,  Yaxu Li  4 ,  Yanrong Yang  4 ,  Zezhi Shan  5  6 ,  Zening Zheng  4 ,  Xin Ge  1 ,  Liang Lin  7 ,  Ping Wang  8  9
Affiliations
  • 1. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 3. Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
  • 4. Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, China.
  • 5. Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 6. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 7. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 8. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
  • 9. Shanghai Frontiers Science Center of Nanocatalytic Medicine, School of Medicine, Tongji University, Shanghai, China. [email protected].
PMID: 40289109 DOI: 10.1038/s41392-025-02219-6
Abstract

Among the leading methods for triggering therapeutic anti-cancer immunity is the inhibition of immune checkpoint pathways. N-glycosylation is found to be essential for the function of various Immune Checkpoint Proteins, playing a critical role in their stability and interaction with immune cells. Removing the N-glycans of these proteins seems to be an alternative therapy, but there is a lack of a de-N-glycosylation technique for target protein specificity, which limits its clinical application. Here, we developed a novel technique for specifically removing N-glycans from a target protein on the cell surface, named deglycosylation targeting chimera (DGlyTAC), which employs a fusing protein consisting of Peptide-N-glycosidase F (PNGF) and target-specific nanobody/affibody (Nb/Af). The DGlyTAC technique was developed to target a range of glycosylated surface proteins, especially these immune checkpoints-CD24, CD47, and PD-L1, which minimally affected the overall N-glycosylation landscape and the N-glycosylation of Other representative membrane proteins, ensuring high specificity and minimal off-target effects. Importantly, DGlyTAC technique was successfully applied to lead inactivation of these immune checkpoints, especially PD-L1, and showed more potential in Cancer Immunotherapy than inhibitors. Finally, PD-L1 targeted DGlyTAC showed therapeutic effects on several tumors in vivo, even better than PD-L1 antibody. Overall, we created a novel target-specific N-glysocylation erasing technique that establishes a modular strategy for directing membrane proteins inactivation, with broad implications on tumor immune therapeutics.

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