The standard of care for glioblastoma has changed little in decades, and the disease remains fundamentally incurable, underscoring the need for new therapeutic strategies that address both tumor-intrinsic resistance and immunosuppressive interactions in the tumor microenvironment. While immune cells are recognized as key drivers of glioblastoma progression, the contribution of platelets, which are elevated and hyperreactive in many patients and correlate with worse outcomes, is poorly understood. This ASPIRE Award tackles the overarching question of how platelet–immune crosstalk shapes immunosuppression in glioblastoma and whether sex-specific biology contributes to clinically meaningful differences in tumor behavior and therapeutic response.
The team will build on preliminary data indicating that thrombin-driven signaling through protease-activated receptor 4 (PAR4) promotes platelet activation and suppresses intratumoral CD8+ T cell number and function in a sex-dependent manner by defining the mechanisms that establish these differences. Using integrated mouse glioblastoma models, genetic and pharmacologic perturbations, immune profiling, and spatial transcriptomic readouts, they will map how platelet–T cell interactions influence tumor growth and response and dissect the roles of sex hormones and sex chromosome complement in these pathways. Complementary assays using human platelets and CD8+ T cells will provide translational validation. By positioning platelets and PAR4 as actionable immunoregulatory nodes, this project offers a clear line of sight toward repurposing next-generation PAR4 inhibitors to improve outcomes for glioblastoma patients, while informing biologically grounded, sex-aware precision strategies.