Inhibiting macrophage-derived lactate transport restores cGAS-STING signaling and enhances anti-tumour immunity in glioblastoma

Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4–MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS–STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM. Overall design: Comparative gene expression profiling analysis of RNA-seq data for MES28 cell and its KD and rescued derivatives (shMCT1/shKU70/KU70-WT/KU70-MU).