Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy

• DOI: 10.1007/s00262-023-03603-3
• Publication Date: 2024-02-13T15:02:26Z
• Authors: Jianying Li; Anjun Ma; Ruohan Zhang; Yao Chen; Chelsea Bolyard; Bao Zhao; Cankun Wang; Thera Pich; Wantong Li; Nuo Sun; Qin Ma; Haitao Wen; Steven K. Clinton; William E. Carson; Zihai Li; Gang Xin
• Keywords: Macrophage polarization; Immune checkpoint; Cancer Immunotherapy

Abstract Introduction As one of the major components tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity cancer. However, a plethora mechanisms have been described differentiation in cancer, metabolic switches to program property TAMs are elusive. Materials methods From unbiased analysis single-cell transcriptome data multiple models, we discovered that uniquely express elevated levels specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation GPR84 mice leads impaired pro-inflammatory polarization macrophages, while their anti-inflammatory phenotype. By contrast, activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates via enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards growth increases anti-tumor efficacy anti-PD-1 Conclusion Overall, report previously unappreciated GPR84, serves as sensing switch orchestrating macrophage polarization. Pharmacological agonists hold promise reshape reverse immunosuppressive TME, thereby restore responsiveness cancer overcome resistance blockade.