Glucose-driven histone lactylation promotes monocyte-derived macrophages in glioblastoma

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.