Development of glucagon-like Peptide-1 lysosomal targeting chimeras for degradation of extracellular and membrane proteins.

Lysosome-targeting chimeras (LYTAC) represent a revolutionary technology for targeted protein degradation. However, the scarcity of highly efficient lysosomal transport receptors poses a major bottleneck to LYTAC advancement. In previous studies, we identified the glucagon-like peptide-1 receptor (GLP-1R) as a novel lysosomal transport receptor that promotes the degradation of membrane proteins. Here, leveraging the stability of semaglutide, we developed GLP-1R-mediated lysosomal-targeting chimeras (g-LYTAC), including antibody-peptide conjugate-based chimeras (APCTACs) targeting epidermal growth factor receptor (EGFR) and programmed cell death ligand 1 (PD-L1), and peptide-peptide conjugate-based chimeras (PPCTACs) targeting integrin. Optimized g-LYTAC exhibit enhanced potency in eliminating cell-surface targets, with efficacy dependent on GLP-1R expression and lysosomal activity. Specifically, APCTAC enhances T cell-mediated cytotoxicity against tumor cells. In mouse models, APCTAC mediates robust PD-L1 degradation, driving tumor-specific immune responses by converting the immunosuppressive tumor microenvironment into an immunostimulatory one. Notably, immune-checkpoint degradation therapy with APCTAC achieves comparable or superior antitumor efficacy while causing significantly less inflammatory damage than antibody therapy. This peptide-based LYTAC system offers a safer, minimally invasive strategy for cancer immunotherapy by combining immune-checkpoint degradation with immunomodulation, laying the groundwork for the development of peptide-based LYTAC as an effective cancer therapy.