Molecular control of platelet extravasation into tumors and its impact on tumor growth.

Platelets are considered intravascular effectors of hemostasis, yet growing evidence indicates that they can migrate across the endothelium. Whether platelet exit from the vasculature is a regulated process analogous to leukocyte trafficking and how migration is coordinated with effector functions has remained unclear. Using genetic, pharmacologic, and imaging approaches, we define the molecular program governing platelet transendothelial migration into tumors in vivo. CXCL12-CXCR4 signaling contributed to platelet extravasation in vivo, with stromal rather than tumor-derived CXCL12 acting as the dominant cue; CXCR4 disruption reduced platelet infiltration and tumor growth. Efficient vascular exit required platelet focal adhesion kinase and platelet endothelial cell adhesion molecule 1, implicating cytoskeletal remodeling and junctional adhesion. Platelet trafficking was uncoupled from effector activity: Munc13-4-dependent dense granule secretion was dispensable for extravasation but required for growth promotion, whereas Munc18-2-regulated α-granule release preserved vascular integrity and restricted passage. Disruption of the CLEC-2/podoplanin axis destabilized vessels and increased leakage. Together, these findings establish regulated platelet extravasation.