SDC4 is a cell surface proteoglycan that regulates exosome biogenesis in concert with SDCBP and PDCD6IP 1. Beyond its canonical exosomal functions, SDC4 serves as a critical receptor in multiple pathogenic pathways. In hepatocellular carcinoma, SDC4 functions as a surface receptor for small extracellular vesicle-bound GPNMB, mediating CD8+ T cell inhibition 2. In colorectal cancer, SDC4 acts as a receptor for midkine (MDK), facilitating regulatory T cell accumulation and immunosuppression within the tumor microenvironment 3. SDC4 is implicated in gastric cancer progression through the ANGPTL4-SDC4 axis, where endothelial cell-derived signals promote tumor invasiveness and migration 4. In papillary thyroid carcinoma, fibronectin-SDC4 interactions contribute to cellular transitions associated with reduced relapse-free survival 5. Clinically, SDC4 demonstrates disease relevance across multiple contexts: it is strongly associated with nonhealing diabetic foot ulcers 6, and SDC4 fusions with NRG1 occur in cholangiocarcinoma and represent therapeutic targets for ErbB-directed inhibitors 78. During early primate gastrulation, SDC4 is a primate-specific marker of anterior visceral endoderm specification 9. These findings establish SDC4 as a multifunctional receptor mediating both developmental processes and tumor-promoting immune interactions.