PMID- 37967215
OWN - NLM
STAT- MEDLINE
DCOM- 20231127
LR  - 20240214
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 120
IP  - 47
DP  - 2023 Nov 21
TI  - NMDAR antagonists suppress tumor progression by regulating tumor-associated 
      macrophages.
PG  - e2302126120
LID - 10.1073/pnas.2302126120 [doi]
LID - e2302126120
AB  - Neurotransmitter receptors are increasingly recognized to play important roles in 
      anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate 
      receptor (NMDAR) on macrophages was reported, but the role of NMDAR on 
      macrophages in the tumor microenvironment (TME) remains unknown. Here, we show 
      that the activation of NMDAR triggered calcium influx and reactive oxygen species 
      production, which fueled immunosuppressive activities in tumor-associated 
      macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. 
      NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these 
      processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking 
      NMDAR functionally and metabolically altered TAM phenotypes, such that they could 
      better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. 
      Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to 
      the elimination of the majority of established preclinical liver tumors. Thus, 
      our study uncovered an unknown role for NMDAR in regulating macrophages in the 
      TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for 
      tumor immunotherapy.
FAU - Yuan, Dongchen
AU  - Yuan D
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Hu, Jing
AU  - Hu J
AUID- ORCID: 0000-0001-6072-5597
AD  - Department of Bioinformatics, School of Life Sciences, Xuzhou Medical University, 
      Xuzhou, Jiangsu 221004, China.
AD  - Department of Genetics, Xuzhou Engineering Research Center of Medical Genetics 
      and Transformation, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Ju, Xiaoman
AU  - Ju X
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Putz, Eva Maria
AU  - Putz EM
AUID- ORCID: 0000-0002-9990-4477
AD  - St. Anna Children's Cancer Research Institute, Medical University of Vienna, 
      Vienna 1210, Austria.
FAU - Zheng, Simin
AU  - Zheng S
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Koda, Stephane
AU  - Koda S
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Sun, Guowei
AU  - Sun G
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Deng, Xiaoran
AU  - Deng X
AD  - Jiangsu Province Key Laboratory in Anesthesiology, School of Anesthesiology, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Xu, Zhipeng
AU  - Xu Z
AUID- ORCID: 0000-0002-8853-5303
AD  - Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern 
      Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
FAU - Nie, Wei
AU  - Nie W
AD  - Department of Pulmonary Medicine, Shanghai Chest Hospital, School of Medicine, 
      Shanghai Jiao Tong University, Shanghai 200240, China.
FAU - Zhao, Yang
AU  - Zhao Y
AUID- ORCID: 0000-0001-8814-7004
AD  - Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia 
      Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 
      Jiangsu 210023, China.
AD  - Department of Biochemistry and Molecular Biology, School of Medicine and Holistic 
      Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 
      210023, China.
FAU - Li, Xianyang
AU  - Li X
AD  - Department of Research and Development, OriCell Therapeutics Co. Ltd, Shanghai 
      200131, China.
FAU - Dougall, William C
AU  - Dougall WC
AD  - Translational Oncology Discovery Group, QIMR Berghofer Medical Research 
      Institute, Brisbane 4702, Australia.
FAU - Shao, Simin
AU  - Shao S
AUID- ORCID: 0000-0002-9662-367X
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Chen, Yan
AU  - Chen Y
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Tang, Renxian
AU  - Tang R
AUID- ORCID: 0000-0002-4205-1071
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Zheng, Kuiyang
AU  - Zheng K
AUID- ORCID: 0000-0002-1896-7485
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
FAU - Yan, Juming
AU  - Yan J
AUID- ORCID: 0000-0003-0857-8870
AD  - Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity 
      and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, 
      Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
LA  - eng
GR  - P 32001/FWF_/Austrian Science Fund FWF/Austria
PT  - Journal Article
DEP - 20231115
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - W8O17SJF3T (Memantine)
SB  - IM
MH  - Humans
MH  - Tumor-Associated Macrophages
MH  - Neoplastic Processes
MH  - Memantine
MH  - *Liver Neoplasms
MH  - *Sarcoma
MH  - Tumor Microenvironment
PMC - PMC10666127
OTO - NOTNLM
OT  - NMDA receptor
OT  - ROS
OT  - macrophages
OT  - tumor
OT  - tumor microenvironment
COIS- X.L. is an employee of OriCell Therapeutics. W.C.D. is a member of the EpimAb 
      Biotherapeutics scientific advisory board and holds patents related to the 
      Receptor Activator of Nuclear Factor-kappa B Ligand (RANKL) pathway. No potential 
      conflicts of interest were disclosed by the other authors.
EDAT- 2023/11/15 18:41
MHDA- 2023/11/27 12:42
PMCR- 2024/05/15
CRDT- 2023/11/15 14:13
PHST- 2024/05/15 00:00 [pmc-release]
PHST- 2023/11/27 12:42 [medline]
PHST- 2023/11/15 18:41 [pubmed]
PHST- 2023/11/15 14:13 [entrez]
AID - 202302126 [pii]
AID - 10.1073/pnas.2302126120 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2023 Nov 21;120(47):e2302126120. doi: 
      10.1073/pnas.2302126120. Epub 2023 Nov 15.