Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma

• DOI: 10.1016/j.immuni.2024.04.006
• Publication Date: 2024-05-03T14:31:51Z
• Authors: Alessandra De Leo; Alessio Ugolini; Xiaoqing Yu; Fabio Scirocchi; Delia Scocozza; Barbara Peixoto; Angelica Pace; Luca D’Angelo; James K.C. Liu; Arnold B. Etame; Aurelia Rughetti; Marianna Nuti; Antonio Santoro; Michael A. Vogelbaum; Jose R. Conejo-Ga...; Paulo C. Rodriguez; Filippo Veglia
• Keywords: Anaerobic glycolysis; Monocyte

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.