Platelets drive immune suppression and glioblastoma growth in a sex-dependent manner via PAR4 signaling

Sex differences in cancer outcomes, including glioblastoma (GBM), are shaped by biological, hormonal, and immune factors, influencing disease progression, treatment responses, survival, and the tumor microenvironment (TME). Platelets, as key regulators of immune responses and tumor progression, may contribute to these sex-based differences by influencing the dynamics of the TME, however, the precise molecular mechanisms remain unclear. Here, we show that GBM patients exhibit heightened platelet reactivity driven by protease-activated receptor 4 (PAR4) signaling. In murine GBM models, targeting PAR4 with BMS986120 prolongs survival in females but not males. This survival advantage is estrogen-dependent and TME-specific, driven by enhanced CD8+ T cell infiltration within the tumor. Inhibiting platelet PAR4 signaling decreases platelet alpha-granule secretion in female tumor-bearing mice while enriching alternative exocytosis pathways, thereby influencing CD8+ T cell activity. PAR4-activated platelets within the TME suppress CD8+ T cell function and CD8+ T cell depletion eliminates the tumor induced platelet reactivity and survival benefit when PAR4 is inhibited. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.