Recently, a research team led by Professor Xiuxing Wang from the School of Basic Medical Sciences at Nanjing Medical University (NMU) published an original research paper entitled “Inhibiting macrophage-derived lactate transport restores cGAS-STING signaling and enhances antitumour immunity in glioblastoma” in Nature Cell Biology.
This study uncovers a novel mechanism of lactate shuttling between macrophages and glioblastoma stem cells (GSCs) within the tumor microenvironment, revealing that lactate-induced lactylation promotes GSC proliferation while remodeling an immunosuppressive niche, thereby identifying blockade of lactate transport or lactylation-associated proteins as a highly translatable immunotherapeutic strategy for glioblastoma .
Glioblastoma (GBM) is the most aggressive primary malignant tumor of the central nervous system, and its high malignancy is largly driven by a complex tumor microenvironment. Glioblastoma stem cells (GSCs)—the core “engine” of this niche—represent a small subpopulation of tumor cells that display the fundamental features of stem cells, including self-renewal, , tumor initiation capability and immune evasion. GSCs also undergo a distinctive metabolic reprogramming, relying on aerobic glycolysis (the Warburg effect) to generate large amounts of lactate.
Conventionally, tumor-derived lactate has been regarded as an immunosuppressive metabolite, exerting its effects primarily through acidification of the tumor microenvironment or inhibition of antitumor immune cells. However, the newly identified post-translational modification known as lactylation enables the covalent attachment of a lactyl group to histones or non-histone proteins, thereby directly modulating gene expression and protein function and conferring on lactate a newly recognized role as a signaling molecule.
Previous studies have largely focused on lactate generated by tumor cell glycolysis, whereas the metabolic characteristics of non-malignant components within the tumor microenvironment remain poorly understood. Whether lactate derived from non-tumor cells can regulate GSC stemness, metabolism, or immune evasion via lactylation, and the mechanisms underlying such regulation, remain to be explored.
To address these challenges, the research team performed single-cell transcriptomic profiling of GBM patient samples and revealed aberrant enrichment of glycolytic signatures in macrophages, with the lactate-efflux transporter MCT4 highly expressed in these cells, whereas the lactate-influx transporter MCT1 was markedly up-regulated in stem-like tumor cells.
Using an in vitro co-culture system of GSCs with macrophage-conditioned medium, together with an in vivo myeloid-specific conditional knockout mouse model (Slc16a3fl/flLyz2Cre), the researchers demonstrated that macrophages secrete lactate via MCT4 to reinforce GSC stemness, while GSCs import this macrophage-derived lactate through MCT1 to sustain their proliferation and self-renewal. Lactate is shuttled between macrophages and GSCs through the MCT1-MCT4 axis.
Further analysis identified a prominent lactylation site at lysine 317 (K317) of KU70, a core component of the non-homologous end-joining (NHEJ) pathway in GSCs. Importantly, blocking lactate uptake in GSCs or inhibiting KU70 lactylation led to massive cytosolic leakage of double-stranded DNA, rapid phosphorylation-mediated activation of the cGAS-STING pathway, and robust secretion of type I interferons, resulting in markedly increased CD8+ T-cells infiltration within the tumor microenvironment.
Based on these findings, dual pharmacological inhibition of MCT1-MCT4 with syrosingopine, or treatment with cell-penetrating peptides designed to disrupt KU70 K317 lactylation, synergized with PD-1 blockade to enhance CD8+ T-cell infiltration and antitumor efficacy, providing a theoretical foundation for clinical translation.
This study unveils an MCT1-MCT4-mediated lactate shuttle between macrophages and GSCs. By importing extracellular lactate, GSCs enhance lactylation of the NHEJ repair KU70 protein, thereby accelerating proliferation and self-renewal, and provides the first proof-of-concept that cell-penetrating peptides targeting the KU70 lactylation site represent a feasible therapeutic strategy for GBM. By integrating tumor metabolism, epigenetic modification, and immune evasion, this study offers a translatable target for converting “cold” tumors into “hot” and opens a new therapeutic avenue for the treatment of the notoriously refractory brain malignancy glioblastoma.
Professor Xiuxing Wang (School of Basic Medical Sciences, NMU), Professor Jeremy N. Rich (University of North Carolina at Chapel Hill), Associate Professor Qian Zhang (School of Basic Medical Sciences, NMU), Professor Xu Qian (School of Public Health, NMU), and Professor Junxia Zhang (Department of Neurosurgery the First Affiliated Hospital with Nanjing Medical University), are co-corresponding authors of this paper. Daqi Li (Ph.D.), Gaoyuan Cui (graduate student), Dr. Kailin Yang (University of Iowa), Chenfei Lu (Ph.D.), Yuhan Jiang (graduate student), and Le Zhang (Analysis Center, NMU), are co-first authors.
This study is supported by the National High-Level Talent Youth Program, the National Natural Science Foundation of China Youth Science Fund (Class A), the National Natural Science Foundation of China General Program, and the Jiangsu Province Distinguished Professor Program.
Link to the original article: https://www.nature.com/articles/s41556-025-01839-y
(Drafted by Professor Xiuxing Wang’s Team; Translation revised by Bei Zhang)
