Tissue factor pathway inhibitor 2 (TFPI2), a serine protease inhibitor, plays a multifaceted role in tumor metastasis. Traditionally viewed as a metastasis suppressor, it inhibits extracellular matrix (ECM) remodeling, epithelial-mesenchymal transition, and angiogenesis. However, emerging evidence indicates that TFPI2 promotes tumor progression in glioblastoma, melanoma, and other cancers by fostering an immunosuppressive tumor microenvironment, mediating pathological ECM remodeling, and enhancing angiogenesis and hematogenous dissemination. Notably, even within the same metastatic cascade, TFPI2 exhibits divergent expression patterns and context-dependent opposing functions, acting either as a metastasis suppressor or promoter. This review summarizes its context-dependent regulatory mechanisms, investigates the underlying basis from structural duality, microenvironmental heterogeneity, and receptor differences, and evaluates its potential as a therapeutic target. Future research should elucidate spatiotemporal microenvironmental dynamics to support early screening and precise intervention.
Guo et al. (Sat,) studied this question.