Hypoxia-driven histone lactylation reprograms immunosuppressive neutrophils within the glioblastoma tumor micro-environment 2119

Description Elevated neutrophils (Neu) infiltration correlates with poor cancer prognosis and resistance to immunotherapies; however, the mechanisms underlying Neu reprogramming remain elusive. By using glioblastoma, we found that Neu suppress T cell functions in mouse and human tumor tissues, contrasting with their non-regulatory phenotype in the periphery. Notably, the immunosuppressive ability of tumor-infiltrating Neu was restricted to a highly glycolytic subset, expressing CD71. Mechanistically, hypoxia boosted the glucose metabolism selectively in CD71+Neu, causing high production of intracellular lactate and lactylation of histone lysine residues, which directly regulated the expression of arginase 1 (ARG1), a key mediator of 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, abolished the immunosuppressive activity of CD71+Neu. Targeting histone lactylation with isosafrole blocked the immunosuppressive ability of CD71+Neu, delayed tumor progression and sensitized brain tumors to immunotherapy. Furthermore, a distinctive gene signature characterizing CD71+Neu correlated with adverse clinical outcomes across diverse human malignancies. Thus, we identified hypoxia-induced histone lactylation as a critical modulator of Neu pro-tumoral functions, providing a potential therapeutic strategy to counteract tumor-induced immunosuppression.