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Updated: Jul 16, 2025

A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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Pro-phagocytic function and structural basis of GPR84 signaling

Xuan Zhang1,2, Yujing Wang1, Shreyas Supekar3

  • 1Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

Nature Communications
|September 14, 2023
PubMed

Insights

GPR84 activation enhances macrophage phagocytosis of cancer cells, particularly when combined with CD47 blockade. This study reveals the GPR84 structure, offering insights into its signaling and potential drug development for cancer therapy.

Area of Science:

  • Immunology
  • Structural Biology
  • Pharmacology

Background:

  • GPR84 is a G protein-coupled receptor (GPCR) activated by medium-chain fatty acids (MCFAs).
  • GPR84 signaling is primarily pro-inflammatory and promotes macrophage phagocytosis.
  • Targeting GPR84 presents a potential strategy for cancer immunotherapy.

Purpose of the Study:

  • To investigate the synergistic effect of GPR84 activation and CD47 blockade on cancer cell phagocytosis.
  • To determine the high-resolution structure of the GPR84-Gi signaling complex.
  • To elucidate the molecular mechanisms underlying GPR84 activation, ligand binding, and selectivity.

Main Methods:

  • Utilized a synthetic GPR84 agonist (6-OAU) and CD47 blockade in cancer cell-macrophage co-cultures.
  • Determined the crystal structure of the GPR84-Gi signaling complex.
  • Performed computational docking and molecular simulations.

Main Results:

  • GPR84 activation synergizes with CD47 blockade to enhance macrophage-mediated cancer cell phagocytosis.
  • The determined structure reveals an occluded 6-OAU binding pocket and an unusual Gi-coupling interface.
  • Structural and computational data suggest mechanisms for MCFA selectivity and ligand interaction with GPR84.

Conclusions:

  • GPR84 plays a significant role in modulating macrophage phagocytic activity against cancer cells.
  • The high-resolution structure provides critical insights into GPR84 activation and signaling pathways.
  • This research lays the groundwork for developing novel GPR84-targeted therapeutics for cancer treatment.

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