Caged Glycan-AntibodyConjugates for Tumor-SelectiveActivation of Lysosome-Targeting Chimeras

Abstract Lysosome-targeting chimeras (LYTACs) induce lysosomal degradation of extracellular and membrane proteins by bridging target proteins with lysosomal trafficking receptors. However, conventional LYTACs often suffer from off-tissue effects, whereas reported tissue-specific LYTACs typically display limited degradation efficiency. To address these challenges, we report a chemically activatable LYTAC platform that leverages tumor microenvironment-specific cues to achieve precise and safe protein degradation in vivo. We designed a glutathione (GSH)-responsive caged mannose-6-phosphate glycan, GSH-pM6P, which was selectively activated within tumor microenvironments characterized by elevated GSH levels. Based on this design, GSH-pM6P was conjugated to an anti-PD-L1 antibody to construct a prodrug-type Pro-LYTAC. In a triple-negative breast cancer mouse model, Pro-LYTAC selectively degraded PD-L1 within tumor tissues, effectively inhibited tumor growth, and markedly reduced hepatic off-target toxicity. Collectively, Pro-LYTAC enabled tumor-specific degradation of target proteins, significantly enhancing the safety and therapeutic window of lysosome-targeted degradation strategies in cancer therapy.