%0 Journal Article
%T Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.
%A De Leo A
%A Ugolini A
%A Yu X
%A Scirocchi F
%A Scocozza D
%A Peixoto B
%A Pace A
%A D'Angelo L
%A Liu JKC
%A Etame AB
%A Rughetti A
%A Nuti M
%A Santoro A
%A Vogelbaum MA
%A Conejo-Garcia JR
%A Rodriguez PC
%A Veglia F
%J Immunity
%V 57
%N 5
%D 2024 May 14
%M 38703775
%F 43.474
%R 10.1016/j.immuni.2024.04.006
%X 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.