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NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages

Dongchen Yuan1, Jing Hu2,3, Xiaoman Ju1

  • 1Department 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.

Proceedings of the National Academy of Sciences of the United States of America
|November 15, 2023
PubMed

Insights

N-methyl-D-aspartate receptors (NMDARs) on tumor-associated macrophages promote immune suppression. Blocking NMDARs enhances anti-tumor immunity and eliminates liver tumors when combined with PD-1 blockade.

Area of Science:

  • Immunology
  • Neuroscience
  • Oncology

Background:

  • Neurotransmitter receptors are crucial in anti-tumor immunity.
  • The role of N-methyl-D-aspartate receptors (NMDARs) on tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) is not well understood.

Purpose of the Study:

  • To investigate the function of NMDARs on macrophages within the TME.
  • To explore the potential of NMDAR antagonists as an immunotherapy strategy for liver cancer.

Main Methods:

  • Utilized hepatocellular sarcoma and fibrosarcoma models.
  • Administered NMDAR antagonists (MK-801, memantine, magnesium).
  • Performed single-cell RNA sequencing analysis.
  • Combined NMDAR antagonists with anti-PD-1 antibody treatment.

Main Results:

  • NMDAR activation in TAMs increased calcium influx and reactive oxygen species, promoting immunosuppression.
  • NMDAR antagonists suppressed these immunosuppressive activities in TAMs.
  • Blocking NMDARs altered TAM phenotypes to enhance T cell and NK cell-mediated anti-tumor immunity.
  • Combination therapy with NMDAR antagonists and anti-PD-1 antibody eradicated established liver tumors.

Conclusions:

  • NMDARs play a previously unrecognized role in regulating macrophage immunosuppression within the TME.
  • Targeting NMDARs represents a promising therapeutic strategy for hepatocellular sarcoma and potentially other cancers.
  • Combined NMDAR antagonism and PD-1 blockade can effectively eliminate established tumors.
Keywords:
NMDA receptorROSmacrophagestumortumor microenvironment

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