Blockade of the Phagocytic Receptor MerTK on Tumor-Associated Macrophages Enhances P2X7R-Dependent STING Activation by Tumor-Derived cGAMP

Immunity. 2020 Feb 18;52(2):357-373.e9. doi: 10.1016/j.immuni.2020.01.014. Epub 2020 Feb 11.


Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Stinggt/gt mice, but not in Cgas-/- mice. Abolishing cGAMP production in Cgas-/- tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.

Keywords: MerTK; P2X7R; STING; cGAS; cancer immunotherapy; efferocytosis; innate immunity; tumor-associated macrophage; type I IFN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis
  • B7-H1 Antigen / immunology
  • Cells, Cultured
  • Female
  • Immunity, Innate
  • Immunotherapy
  • Interferon Type I / metabolism
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Nucleotides, Cyclic / metabolism*
  • Nucleotidyltransferases / deficiency
  • Nucleotidyltransferases / metabolism
  • Phagocytosis
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Purinergic P2X7 / deficiency
  • Receptors, Purinergic P2X7 / metabolism*
  • Signal Transduction / immunology
  • Xenograft Model Antitumor Assays
  • c-Mer Tyrosine Kinase / genetics
  • c-Mer Tyrosine Kinase / immunology*


  • B7-H1 Antigen
  • Interferon Type I
  • Membrane Proteins
  • Nucleotides, Cyclic
  • P2rx7 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Purinergic P2X7
  • Sting1 protein, mouse
  • cyclic guanosine monophosphate-adenosine monophosphate
  • Adenosine Triphosphate
  • Mertk protein, mouse
  • c-Mer Tyrosine Kinase
  • Nucleotidyltransferases
  • cGAS protein, mouse