2. Academic Validation
  3. Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming

Medium-Chain Fatty Acid Receptor GPR84 Modulates Cytotoxic CD8 T cells Antitumor Immunity Through Metabolic Reprogramming

  • Cancer Immunol Res. 2026 Jan 20. doi: 10.1158/2326-6066.CIR-25-0695.
Phaethon Philbrook 1,  Matthew J Dean 1,  Maria Dulfary Sanchez-Pino 1,  Li Qin Zheng 2,  Jovanny Zabaleta 2,  Julio A Vázquez-Martínez 3,  Darwin Chang 3,  Jessica K Mandula 3,  Timothy I Shaw 4,  Dorota Wyczechowska 2,  Jone Garai 5,  Ramesh Thylur Puttalingaiah 1,  Amirsalar Mansouri 6,  Weishan Huang 7,  Satyajit Das 8,  Shiun Chang 9,  Jose R Conejo-Garcia 10,  Paulo C Rodriguez 3,  Augusto C Ochoa 2
Affiliations

Affiliations

  • 1 Louisiana State University Health Sciences Center New Orleans New Orleans, LA United States.
  • 2 Louisiana State University Health Sciences Center New Orleans, LA United States.
  • 3 Moffitt Cancer Center Tampa, FL United States.
  • 4 Moffitt Cancer Center Tampa United States.
  • 5 Louisiana State University Health Sciences Center New Orleans United States.
  • 6 Louisiana State University Health Sciences Center New Orleans New Orleans, Louisiana United States.
  • 7 Louisiana State University United States.
  • 8 Medical University of South Carolina Charleston, SC United States.
  • 9 H. Lee Moffitt Cancer Center and Research Institute Tampa, FL United States.
  • 10 Duke University Durham, NC United States.
PMID: 41557755 DOI: 10.1158/2326-6066.CIR-25-0695
Abstract

GPR84 is a medium-chain Free Fatty Acid Receptor predominantly expressed in myeloid cells. Previous studies have identified GPR84 as an enhancer of the pro-inflammatory myeloid cell responses and a regulator of metabolic homeostasis. However, the role of GPR84 in T cell function and metabolism remains largely unexplored. This study tested the effect of GPR84 modulation on CD8+ T cell function and metabolism in vitro and examined its effect on antitumor function in adoptive cellular therapy models. Pharmacological antagonism with GLPG1205 or genetic deletion of GPR84 promoted T cell differentiation, proliferation, cytokine production, and cytotoxicity, whereas agonism with DL175 reduced these functions. These functional changes were paralleled by changes in metabolic activity. Antagonism and genetic deletion increased glucose uptake, glycolysis, Oxidative Phosphorylation, and ATP production, which enhanced the overall cell energetic fitness, whereas agonism resulted in a quiescent energetic profile. Furthermore, antagonism or deletion of GPR84 in antigen-specific CD8+ T cells in adoptive cellular therapy models enhanced their antitumor effects in vivo. Thus, GPR84 inhibition improves CD8+ T cell function and may further enhance adoptive cellular therapies.

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