PTPRS is a cell surface receptor tyrosine phosphatase that regulates neurite outgrowth and immune homeostasis through binding to glycosaminoglycans on proteoglycans. The receptor binds chondroitin sulfate proteoglycans and heparan sulfate proteoglycans with opposing functional consequences: chondroitin sulfate promotes inhibition of axonal growth, while heparan sulfate proteoglycans stimulate neurite outgrowth. PTPRS dephosphorylates neurotrophic receptor kinases and downregulates signaling through Akt and mitogen-activated protein kinase pathways. The receptor also suppresses toll-like receptor 9-mediated activation of nuclear factor kappa-B and production of type I interferons in plasmacytoid dendritic cells, preventing spontaneous immune activation and intestinal inflammation. In Alzheimer's disease, a protective PTPRS variant correlates with higher transcript abundance, lower phosphorylated tau in cerebrospinal fluid, and preserved synaptic integrity markers; male carriers show a 10-month delay in disease onset 1. PTPRS loss drives aggressive phenotypes in several cancers: in glioblastoma, PTPRS deficiency enhances metastatic capability and temozolomide resistance through MAPK-MEK-ERK signaling 2, while reduced expression in neurofibromas promotes epithelial-mesenchymal transition via EGFR signaling 3. Therapeutic strategies targeting PTPRS include monoclonal antibodies blocking its interaction with syndecan-4 heparan sulfate proteoglycans to activate the receptor in rheumatoid arthritis 4, and neoantigen-targeted vaccines exploiting conserved PTPRS mutations across colorectal, endometrial, gastric, and prostate cancers 5.