Journal article
Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma
Nature cell biology
01/06/2026
DOI: 10.1038/s41556-025-01839-y
PMID: 41495200
Abstract
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.
Details
- Title: Subtitle
- Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma
- Creators
- Daqi Li - University of North Carolina at Chapel HillGaoyuan Cui - Nanjing Medical UniversityKailin Yang - University of IowaChenfei Lu - Nanjing Medical UniversityYuhan Jiang - Nanjing Medical UniversityLe Zhang - Nanjing Medical UniversityQiulian Wu - UNC Lineberger Comprehensive Cancer CenterDeobrat Dixit - Columbia University Irving Medical CenterZhe Zhu - Columbia University Irving Medical CenterRyan C Gimple - Washington University in St. LouisDanling Gu - Nanjing Medical UniversityJiancheng Gao - Nanjing Medical UniversityQiankun Lin - Nanjing Medical UniversityHang Yu - Nanjing Medical UniversityZhumei Shi - Nanjing Medical UniversityYun Chen - Jiangsu Cancer HospitalQianghu Wang - Jiangsu Cancer HospitalGuangfu Jin - Jiangsu Cancer HospitalFan Lin - Nanjing Medical UniversityJunfei Shao - Wuxi People's HospitalQigang Zhou - Nanjing Medical UniversityChong Liu - Zhejiang LabChaojun Li - Jiangsu Cancer HospitalYongping You - Jiangsu Province HospitalNu Zhang - Sun Yat-sen UniversityJunxia Zhang - Nanjing Medical UniversityXu Qian - Jiangsu Cancer HospitalQian Zhang - National Health and Family Planning CommissionJeremy N Rich - University of North Carolina at Chapel HillXiuxing Wang - Jiangsu Cancer Hospital
- Resource Type
- Journal article
- Publication Details
- Nature cell biology
- DOI
- 10.1038/s41556-025-01839-y
- PMID
- 41495200
- NLM abbreviation
- Nat Cell Biol
- ISSN
- 1465-7392
- eISSN
- 1476-4679
- Publisher
- Springer Nature
- Grant note
- 82525047 / National Natural Science Foundation of China (National Science Foundation of China) 82573312 / National Natural Science Foundation of China (National Science Foundation of China)
- Language
- English
- Electronic publication date
- 01/06/2026
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9985116169902771
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