Abstract 6142: Functional reprogramming of neutrophils in the tumor microenvironment

Abstract Despite functional heterogeneity, high frequency of intratumoral neutrophils predicts poor clinical outcome in cancer, including brain tumors. The tumor microenvironment reprograms neutrophils into immunosuppressive subsets that hinder anti-cancer immunity, thereby contributing to tumor growth and poor response to immunotherapy. However, the mechanisms underlying the regulatory reprogramming of neutrophils remain elusive. Here, we report that neutrophils suppress T cell function in mouse and human brain tumor tissues, contrasting with their non-immunosuppressive phenotype in the periphery. The immunosuppressive ability of brain-tumor infiltrating neutrophils was restricted to a subset of highly glycolytic neutrophils expressing the transferrin receptor CD71, which acquired immunosuppressive properties in response to hypoxia. Mechanistically, hypoxia boosted glucose metabolism in CD71+ neutrophils, which was accompanied by high avidity for glucose and production of lactate. Intracellular lactate caused lactylation of histone lysine residues that directly regulated the expression of arginase 1 (ARG1), required for T cell suppression. Pharmacological inhibition of glycolysis, lactate production or the histone lactylation writer CBP/P300, impaired histone lactylation and the expression of ARG1 and, accordingly, reduced the immunosuppressive activity of CD71+ neutrophils. Targeting histone lactylation with the anti-epileptic drug isosafrole blocked the immunosuppressive ability of CD71+ neutrophils, delayed tumor progression and sensitized brain tumors to immunotherapy. Furthermore, a distinctive gene signature characterizing immunosuppressive and glycolytic CD71+ neutrophils correlated with adverse clinical outcomes across diverse human malignancies. Thus, our study identifies hypoxia-driven histone lactylation as a critical determinant of the functional reprogramming of neutrophils within tumors, providing a potential therapeutic strategy to counteract neutrophil-induced immunosuppression. Citation Format: Filippo Veglia, Alessio Ugolini, Alessandra De Leo. Functional reprogramming of neutrophils in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6142.