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

Abstract 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 ( L 2,5 P ) with enhanced degradative efficacy (DC 50 = 156 nM), stability, and pharmacokinetics. HerTAC L 2,5 P 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.