PROS1 encodes protein S, a vitamin-K-dependent anticoagulant plasma protein that functions as a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa 1. This primary anticoagulant role is well-established in hemostasis regulation. Beyond coagulation, PROS1 has emerged as a critical regulator of immune-suppressive tumor microenvironments through interactions with TAM receptors. In glioma, elevated PROS1 expression correlates with increased infiltration of immunosuppressive macrophages and neutrophils while suppressing anti-tumor immune cells, predicting poor prognosis 2. Similarly, in papillary thyroid microcarcinoma, the PROS1-MERTK signaling axis drives tumor progression via paracrine signaling through fibroblast-derived PROS1 3. PROS1 also suppresses tumor immunity through upregulation of immunomodulatory molecules 4. Clinically, heterozygous loss-of-function variants in PROS1 are rare (0.009-0.018% prevalence) but confer markedly elevated venous thromboembolism risk (OR 14.01) with carriers showing 48% reduced plasma protein S levels 1. These variants do not associate with arterial thrombosis. Loss-of-function PROS1 variants appear rarer than acquired protein S deficiency as a cause of thrombophilia. In glioblastoma, PROS1 knockdown induces apoptosis and substantially reduces invasion 5, suggesting therapeutic potential through PROS1 inhibition in specific cancers.