M6PR (mannose-6-phosphate receptor, cation-dependent) functions as a cargo receptor mediating transport of phosphorylated lysosomal enzymes from the Golgi complex and cell surface to lysosomes. 1 Lysosomal enzymes bearing phosphomannosyl residues bind specifically to M6PR in the Golgi apparatus; the resulting receptor-ligand complex is transported to acidic prelysosomal compartments where low pH mediates complex dissociation. M6PR operates through clathrin-coated endocytic vesicles and the retromer complex, with recent studies revealing that retromer-mediated recycling of M6PR to the plasma membrane represents a key regulatory mechanism. 2 M6PR dysfunction has significant disease relevance. CLN3 mutations in Batten disease cause M6PR mis-trafficking, leading to mis-sorting of lysosomal enzymes and defective autophagic-lysosomal reformation. 1 Additionally, M6P biosynthesis deficiency impairs M6PR ligand availability, reducing lysosomal enzyme targeting efficiency. 2 Clinically, M6PR has emerged as a therapeutic target. Lysosome-targeting chimeras (LYTACs) exploit M6PR to direct extracellular proteins for lysosomal degradation, representing a novel degradation platform complementary to traditional inhibitory approaches. 3 LYTACs successfully degrade therapeutically relevant proteins including VEGF, EGFR, and PD-L1 in various disease models. 4 This strategy offers advantages for targeting proteins with inaccessible activity profiles and extends therapeutic reach beyond cytosolic targets.