Tumours often display high levels of lactate, which can, following conversion into lactyl-CoA, be transferred to specific lysine residues on proteins, particularly histones. The mechanisms and effects of this histone lactylation have been incompletely understood. Wang et al. now demonstrate that in glioblastoma, histone lactylation dampens immune responses through CD47-dependent suppression of phagocytosis.

The authors next analysed the possible contribution of macrophages and microglia, which can account for up to half of the glioblastoma cell population, to lactate production. They identified elevated lactate production in immunosuppressive M2-like microglia, which, when co-cultured with GSCs, increased lactate levels and histone lactylation in GSCs. Pretreatment of GSCs with exogenous lactate decreased their phagocytosis by microglia or macrophages, whereas inhibition of lactate production by dichloroacetate (DCA) pretreatment had the opposite effect. Concordant results were obtained in vivo, when tumour-bearing NSG mice were treated with lactate, DCA or controls.