Acrolein- thioredoxin 1- p38 signaling drives neutrophil-mediated immunosuppression and glioblastoma progression

Glioblastoma (GBM) is a highly aggressive type of brain tumor characterized by diffuse infiltration and a profoundly immunosuppressive microenvironment in which polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) derived from neutrophils play a key role. In this study, we investigated how acrolein, a reactive aldehyde that accumulates under oxidative stress, modulates neutrophil redox regulation and promotes their polarization toward an immunosuppressive phenotype. We found that acrolein covalently modifies thioredoxin 1 (TRX1) at Cys35, impairing its activity and activating the apoptosis signal-regulating kinase 1 (ASK1)–p38 signaling cascade. This redox disruption drives neutrophils toward an MDSC-like state, characterized by increased expression of LOX-1 and Arg-1, enhanced COX-2/PGE₂ production, and suppressed CD8⁺ T-cell proliferation. Importantly, pharmacological inhibition of p38 or scavenging of acrolein reversed these effects, restored CD8⁺ T-cell infiltration, and significantly reduced glioma growth in murine models. Clinically, increased frequencies of Acr⁺CD15⁺ and p-p38⁺CD15⁺ neutrophils were associated with decreased CD8⁺ T-cell infiltration and poor patient survival. Mechanistically, this study identifies TRX1 Cys35 as a critical target of acrolein and establishes the activity of the acrolein–TRX1–p38 axis as a novel link between oxidative stress and neutrophil-mediated immunosuppression in GBM. Therefore, targeting this pathway may represent a promising strategy to restore antitumor immunity and counteract immune evasion in glioblastoma.