HerTACs Enable Tumor-Selective Lysosomal Degradation of Membrane and Extracellular Proteins via HER2 Trafficking.

Targeting extracellular and membrane proteins for degradation remains a frontier challenge in the field of targeted protein degradation (TPD), largely due to the intracellular confinement of existing proteolysis systems and reliance on bulky biologics. Here, we develop a novel TPD platform, human epidermal growth factor receptor 2 (HER2)-targeted lysosome-tethering chimeras (HerTACs), which co-opts the tumor overexpressed, endocytic, and lysosomal trafficking capability of HER2. Starting from the HER2-binding peptide LTVSPWY, we engineered the first-generation HerTAC (LP), a conjugate of the HER2-binding peptide and a PD-L1 ligand, to degrade programmed death ligand 1 (PD-L1) in HER2-positive cells. Guided by AlphaFold modeling and alanine scanning, we developed a stapled peptide-based HerTAC (LP) with enhanced degradative efficacy (DC = 156 nM), stability, and pharmacokinetics. HerTAC LP showed potent antitumor activity and low systemic toxicity in HER2 breast cancer animal models. The HerTAC strategy was further extended to other clinically relevant inaccessible membrane and extracellular targets (i.e., V-domain Ig suppressor of T cell activation [VISTA] and macrophage migration inhibitory factor [MIF]), highlighting its generality and broad applicability. This work establishes a tumor-selective, lysosome-directed TPD strategy that expands the druggable proteome and offers a clinically transformable approach for precision oncology.