TFPI2 (Tissue Factor Pathway Inhibitor 2) is a Kunitz-type serine protease inhibitor with dual roles in protease regulation and tumor microenvironment modulation. As a classical protease inhibitor, TFPI2 inhibits trypsin, plasmin, factor VIIa/tissue factor, and weakly factor Xa, potentially regulating plasmin-mediated matrix remodeling 1. Beyond canonical coagulation inhibition, TFPI2 functions as a secreted signaling molecule that promotes glioblastoma stem cell self-renewal via c-Jun N-terminal kinase-STAT3 pathway activation and polarizes microglia toward immunosuppression through CD51-STAT6 signaling 1. In hepatocellular carcinoma, TFPI2 enhances chemosensitivity by stabilizing GADD45A mRNA through CCAR2 interaction, promoting DNA damage and inhibiting homologous recombination repair 2. TFPI2 expression is frequently silenced in cancers through epigenetic mechanisms; LSD1-mediated histone demethylation suppresses TFPI2 in triple-negative breast cancer, while TFPI2 promoter hypermethylation reduces its expression in diabetic atherosclerosis 34. In diabetic atherosclerosis, reduced TFPI2 promotes disease progression by failing to block AP-2α-mediated PPARγ transcription suppression, impairing M2 macrophage polarization 4. Clinically, TFPI2 serves as a noninvasive biomarker: promoter methylation in peripheral blood mononuclear cells shows 88% sensitivity for colorectal cancer detection, while elevated serum TFPI2 correlates with clear cell renal carcinoma severity and metastasis 56.