A sex-specific platelet switch controls anti-tumor immunity in glioblastoma

Sex differences in glioblastoma (GBM) outcomes are shaped by biological, hormonal, and immune factors, but the mechanisms driving these disparities remain unclear. We identify platelet protease-activated receptor 4 (PAR4) signaling as a regulator of sex-specific anti-tumor immunity. GBM patients exhibit increased platelet reactivity driven by PAR4. In murine models, pharmacologic or genetic inhibition of PAR4 prolongs survival in females, but not males, and is estrogen dependent, persisting in hormonal females regardless of chromosomal sex. The survival advantage is mediated within the tumor microenvironment through enhanced CD8⁺ T cell infiltration and function. PAR4-activated platelets suppress CD8⁺ T cell activity, whereas CD8⁺ T cell depletion abolishes both tumor-induced platelet reactivity and the PAR4-dependent survival advantage. Mechanistically, PAR4 inhibition enhances CD8⁺ T cell signaling through interaction with estrogen receptor β (ERβ). These findings demonstrate that platelets are critical regulators of sex-specific anti-tumor immunity and identify PAR4 as a promising therapeutic target in cancer.