Covalently PD-L1 Anchoring Drives Bispecific Nanostructure Assembly for Spatial Control of T Cell Recruitment and...

Area of Science:

• Biochemistry
• Immunology
• Materials Science

Background:

• Immune checkpoint blockade, particularly targeting the PD-1/PD-L1 axis, shows promise in cancer therapy.
• Current methods face challenges in efficiently recruiting and activating T cells while suppressing immune responses.
• Limited focus exists on reprogramming immune functions directly on the tumor cell surface.

Purpose of the Study:

• To develop a novel strategy for precise modification of PD-L1 on the cell surface.
• To engineer artificial topological nanostructures (ATNs) for enhanced T cell-mediated antitumor immunity.
• To investigate the potential of glycan oxidation-driven self-assembly in immune modulation.

Main Methods:

• Utilized a "localized oxidation-covalent assembly" strategy for cell surface PD-L1 modification via glycan oxidation.
• Employed bioorthogonal reactions to induce in situ construction of ATNs.
• Investigated the role of N-glycosylation sites in PD-L1 modification.

Main Results:

• ATNs effectively blocked the PD-1/PD-L1 axis, relieving immune suppression.
• ATNs recruited and activated T cells through transmembrane bridging, mimicking bispecific T cell engagers (BiTEs).
• Demonstrated spatially precise T cell recruitment and activation via PD-L1-dependent localization, enabling programmable immune regulation.

Conclusions:

• Glycan oxidation-driven self-assembly offers a promising approach for immune modulation in cancer therapy.
• The developed ATNs significantly enhance antitumor immune responses.
• This strategy provides a versatile chemical biology tool for precise reprogramming of immune checkpoint functions.