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

Immune checkpoint blockades have shown great potential in cancer therapy. However, achieving efficient recruitment and activation of T cells while blocking immune suppression remains a critical challenge. Current strategies mainly focus on the blockade of the PD-1/PD-L1 axis, with limited attention to reprogramming immune functions on the tumor cell surface. Here, we report a "localized oxidation-covalent assembly" strategy that achieves precise modification of PD-L1 on the cell surface through glycan oxidation, thereby harnessing bioorthogonal reactions to induce the in situ construction of artificial topological nanostructures (ATNs), which subsequently augment T cell-mediated antitumor immunity. ATNs not only block the PD-1/PD-L1 axis to relieve immune suppression but also recruit and activate T cells through transmembrane bridging interactions, mimicking bispecific T cell engagers (BiTEs) and markedly enhancing antitumor immune responses. Mechanistic studies revealed that N-glycosylation sites are critical for probe-mediated aldehyde modification of PD-L1. We further demonstrated that the ATNs achieve spatially precise T cell recruitment and activation via PD-L1-dependent localization, enabling programmable immune regulation. Overall, this approach not only underscores the potential of glycan oxidation-driven self-assembly in immune modulation but also provides a versatile chemical biology tool for the precise reprogramming of immune checkpoint functions.