Acrolein produced by glioma cells under hypoxia inhibits neutrophil AKT activity and suppresses anti-tumoral activities

Acrolein, which is the most reactive aldehyde, is a byproduct of lipid peroxidation in a hypoxic environment. Acrolein has been shown to form acrolein-cysteine bonds, resulting in functional changes in proteins and immune effector cell suppression. Neutrophils are the most abundant immune effector cells in circulation in humans. In the tumor microenvironment, proinflammatory tumor-associated neutrophils (TANs), which are termed N1 neutrophils, exert antitumor effects via the secretion of cytokines, while anti-inflammatory neutrophils (N2 neutrophils) support tumor growth. Glioma is characterized by significant tissue hypoxia, immune cell infil-tration, and a highly immunosuppressive microenvironment. In glioma, neutrophils exert antitumor effects early in tumor development but gradually shift to a tumor-supporting role as the tumor develops. However, the mechanism of this anti-to protumoral switch in TANs remains unclear. In this study, we found that the pro-duction of acrolein in glioma cells under hypoxic conditions inhibited neutrophil activation and induced an anti-inflammatory phenotype by directly reacting with Cys310 of AKT and inhibiting AKT activity. A higher per-centage of cells expressing acrolein adducts in tumor tissue are associated with poorer prognosis in glioblastoma patients. Furthermore, high-grade glioma patients have increased serum acrolein levels and impaired neutrophil functions. These results suggest that acrolein suppresses neutrophil function and contributes to the switch in the neutrophil phenotype in glioma.

Automated summary

Acrolein, a reactive aldehyde, is generated during lipid peroxidation in a hypoxic environment and can form bonds with cysteine residues, leading to functional changes in proteins and immune suppression. Neutrophils play a critical role in the immune response, with proinflammatory N1 neutrophils exerting antitumor effects and anti-inflammatory N2 neutrophils supporting tumor growth. Glioma is characterized by hypoxia, immune cell infiltration, and an immunosuppressive microenvironment. Previous studies have shown that neutrophils exhibit an antitumor phenotype in early glioma development but transition to a tumor-supporting role as the tumor progresses. However, the mechanism behind this switch in neutrophil phenotype remains unclear. This study demonstrates that acrolein production in glioma cells inhibits neutrophil activation and induces an anti-inflammatory phenotype by directly interacting with AKT and inhibiting its activity. Moreover, higher levels of acrolein adducts in tumor tissue are associated with poorer prognosis in glioblastoma patients, and high-grade glioma patients exhibit increased serum acrolein levels and impaired neutrophil functions. These findings highlight the importance of acrolein in suppressing neutrophil function and contributing to the switch in neutrophil phenotype in glioma.