A Single‐Amino‐Acid Ligand for LAT1: A Minimalist and Modular Platform for Lysosome‐Targeted Degradation of Membrane Proteins

ABSTRACT Targeted degradation of membrane proteins via the lysosomal pathway holds great therapeutic promise, yet existing platforms rely on bulky ligands such as glycopolymers, antibodies, or protein nanocages, which complicate synthesis and limit tissue penetration. Here, we repurpose L‑type amino acid transporter 1 (LAT1)—a nutrient transporter overexpressed in diverse cancers—as a lysosomal targeting receptor. Taking advantage of LAT1‘s natural substrate preference, we design a minimalist chemical handle: a single phenylalanine derivative that serves as a high‑affinity LAT1 ligand. This ligand is conjugated via bioorthogonal chemistry to various warheads (antibodies or small molecules) to generate modular degraders termed LAT1‐mediated lysosome‐targeting chimeras (LA‑LYTAC). These chimeras efficiently internalize and route oncogenic membrane proteins—including PD‑L1, EGFR, and integrins—to lysosomes for degradation. The platform operates through a LAT1‑dependent, lysosomal mechanism and suppresses downstream signaling pathways. In a syngeneic mouse model of triple‑negative breast cancer, a PD‑L1‑targeting LA‑LYTAC reduces tumor growth by more than 60%, enhances CD8 + T cell infiltration, and shows no overt toxicity. This work establishes a synthetically accessible, truly modular, and tumor‑selective degradation platform driven by a single amino acid, offering a streamlined alternative to existing lysosome‑targeting technologies.