Abstract

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that represents a significant therapeutic challenge because of its immunosuppressive tumor microenvironment (TME). GBM employs multiple sophisticated mechanisms for immune evasion, including proinflammatory cytokine secretion and immune cell effector function impairment. Due to these complex immune evasion strategies, immunotherapies are effective in only a minority of GBM patients. Herein, we identified P21-activated kinase 4 (PAK4) as a critical immunosuppressive gene that is highly expressed in GBM and actively promotes tumor progression. Mechanistically, PAK4 mediates transforming growth factor-beta 1 (TGF-β1) release from GBM cells, triggering PI3K/AKT/NF-κB signalling pathway activation in CD8 + T cells, which consequently upregulates phospholipase A2 group IVA (PLA2G4A) expression. PLA2G4A activation triggers phosphatidylcholine (PC) depletion in CD8 + T cells, damages mitochondrial and lysosomal functions, inducing subsequent mitophagic flux suppression, which culminates in the functional exhaustion of CD8 + T cells. Furthermore, PLA2G4A inhibitor treatment effectively reduces CD8 + T cell exhaustion while enhancing T cell cytotoxic capacity. Finally, combined PAK4 inhibitor and anti-PD-L1 therapy increases the CD8 + T cell cytotoxic function and suppresses tumor growth. Overall, our study results suggest that targeting PAK4 could be a potential strategy for GBM immunotherapy.