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 (L_2,5P) with enhanced degradative efficacy (DC₅₀ = 156 nM), stability, and pharmacokinetics. HerTAC L_2,5P 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.