IGF2R is a multifunctional membrane receptor with critical roles in lysosomal protein trafficking and growth factor signaling. Primary function involves mannose-6-phosphate (M6P)-mediated transport of phosphorylated lysosomal enzymes from the Golgi complex to lysosomes 1. The receptor binds M6P-tagged cargo in the Golgi apparatus and facilitates receptor-ligand complex transport to acidic prelysosomal compartments, where low pH triggers dissociation; the receptor then recycles via retromer complex binding 1. IGF2R also binds insulin-like growth factor 2 (IGF2), a ligand critical for synaptic plasticity and memory consolidation in the nervous system 2. Beyond canonical trafficking, IGF2R regulates T-cell coactivation through DPP4 binding and modulates microglial lysosomal function by interacting with CD22 3. Disease relevance is substantial: IGF2 deficits via IGF2R dysfunction associate with Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis 2. IGF2R also influences metabolic homeostasis, with gene polymorphisms and circulating IGF2R levels associated with type 2 diabetes susceptibility and insulin resistance 4. Clinically, IGF2R's endocytic capacity enables therapeutic exploitation through designed EndoTags for targeted protein degradation in cancer 5, while blocking IGF2-IGF2R interactions enhances oncolytic viral immunotherapy efficacy 6.