CD109 is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein that functions as a multifunctional immunomodulatory and signaling regulator. Structurally, CD109 is a member of the α2-macroglobulin/C3,C4,C5 family of thioester-containing proteins 1 and can exist as a membrane-anchored form or be shed as soluble CD109 (sCD109) after proteolytic cleavage 2. Primary functions encompass dual roles in TGF-β pathway modulation and immune suppression. CD109 negatively regulates TGF-β signaling in keratinocytes 1 and can enhance EGF signaling in certain cell types 2. Beyond keratinocyte biology, tumor-derived sCD109 orchestrates immunosuppression by reprogramming tumor-associated macrophages through the FcγRI/SYK/NF-κB pathway, promoting CD73+ macrophage enrichment that impairs T-cell responses 3. CD109 also functions as a master regulator of inflammatory responses via TGF-β and NF-κB pathway modulation 4. Clinically, CD109 expression correlates with poor prognosis across multiple malignancies. High CD109 expression associates with unfavorable overall survival in cancer patients 5, particularly in squamous cell carcinomas 6. Additionally, CD109 serves as a host factor for KSHV entry in senescent endothelial cells 7, and facilitates perineural invasion in KRAS-mutant pancreatic cancer through extracellular vesicle-mediated circRNA delivery 8. These findings suggest CD109 inhibition as a therapeutic strategy to enhance immunotherapy efficacy.