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1 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
2 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
4 Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
5 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
6 Analysis Center, Nanjing Medical University, Nanjing, China.
7 Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
8 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
9 Department of Medicine, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
10 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
11 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
12 Department of Neurosurgery of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
13 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China.
14 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou, China.
15 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. zjx232@njmu.edu.cn.
16 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. xqianmedres@njmu.edu.cn.
17 Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. xqianmedres@njmu.edu.cn.
18 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. zhangqian01@njmu.edu.cn.
19 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. zhangqian01@njmu.edu.cn.
20 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. drjeremyrich@gmail.com.
21 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
22 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
23 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
24 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
25 Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
1 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China.
2 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.
3 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
4 Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
5 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
6 Analysis Center, Nanjing Medical University, Nanjing, China.
7 Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
8 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
9 Department of Medicine, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
10 The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
11 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China.
12 Department of Neurosurgery of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
13 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China.
14 Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou, China.
15 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. zjx232@njmu.edu.cn.
16 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. xqianmedres@njmu.edu.cn.
17 Department of Nutrition and Food Hygiene, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. xqianmedres@njmu.edu.cn.
18 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. zhangqian01@njmu.edu.cn.
19 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. zhangqian01@njmu.edu.cn.
20 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. drjeremyrich@gmail.com.
21 National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
22 Institute for Brain Tumours, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
23 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
24 Department of Clinical Pharmacology, School of Pharmacy, Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
25 Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. drxiuxingwang@163.com.
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.
Competing interests: The authors declare no competing interests.
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