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Tumor-associated macrophage derived lactate remodeling glioblastoma stem cells immune microenvironment through lactylation in glioblastoma

ABSTRACT: Glioblastoma (GBM) is a malignancy with the complex tumor microenvironment (TME) dominated by glioblastoma stem cells (GSCs) and infiltrated with tumor-associated macrophages (TAMs), exhibiting aberrant metabolism progress. Lactate is a critical glycolytic metabolite that promotes tumor progression. However, the mechanism of lactate transporting and lactylation in the tumor microenvironment (TME) of GBM remains elusive. Examination of lactate metabolic signature highly expressed on TAMs and tumor cells. We uncovered that TAMs provide lactate to GSCs, promoting GSCs proliferation and inducing the non-homologous end joining (NHEJ) protein KU70 lactylated at K317. Furthermore, TAM-derived lactate-inducing KU70 lactylation inhibits cGAS- type I interferon signaling, remodeling the immunosuppressive microenvironment through reduced cytotoxic CD8+ T cell infiltration, promoting the malignant progress of GBM. This study unveils TAMs-derived lactate and lactylation as a critical regulator of NHEJ, providing fresh insights into how aberrant lactylation and TME reprogramming are linked to DNA damage repair, which contributes to exploring new therapeutic strategies for targeting lactate transporters in combination with anti-PD-1-antibody to enhance anti-tumor immunity, which provides the theoretical basis for improving the clinical prognosis of GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266884 | GEO | 2024/06/01

REPOSITORIES: GEO

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