Platelet-Prostate cancer crosstalk driving disparities and therapeutic vulnerabilities.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among American men. Striking disparities persist in PCa incidence and mortality, with African American (AA) men experiencing a 1.7-fold higher incidence and more than two-fold higher mortality rate compared to European American (EA) men. Despite this disparity, the Black community remains underrepresented in PCa research and clinical trials. As PCa progresses to high-grade and metastatic castration-resistant stages, treatment options become increasingly limited and median overall survival falls below two years, underscoring the urgent need for novel therapeutic strategies. One promising yet underexplored avenue is the circulatory microenvironment, which consists of platelets (PLTs) and immune cells that interact directly with circulating tumor cells (CTCs) during intravasation. Mounting evidence supports a bidirectional relationship in which tumor cells activate platelets to promote thrombosis, and platelets in turn activate tumor cells to promote tumorigenesis. In PCa, reciprocal signaling between tumor cells and platelets is increasingly being recognized. Recent transcriptomic profiling (RNA-Seq) has identified transmembrane signaling proteins mediating these interactions, broadly categorized into four groups: (1) integrin-ligand, (2) EPH receptor-ephrin, (3) immune checkpoint receptor-ligand, and (4) miscellaneous receptor-ligand interactions. Notably, many components of these signaling axes are overexpressed in platelets and/or PCa cells from individuals of African ancestry and are associated with poorer clinical outcomes. These findings highlight platelet-mediated signaling pathways as a source of novel biomarkers and pharmacologically actionable targets, offering opportunities to address both aggressive disease biology and persistent PCa disparities.