{"doi":"10.1007/s00262-023-03603-3","title":"Targeting metabolic sensing switch GPR84 on macrophages for cancer immunotherapy","abstract":"INTRODUCTION: As one of the major components of the tumor microenvironment, tumor-associated macrophages (TAMs) possess profound inhibitory activity against T cells and facilitate tumor escape from immune checkpoint blockade therapy. Converting this pro-tumorigenic toward the anti-tumorigenic phenotype thus is an important strategy for enhancing adaptive immunity against cancer. However, a plethora of mechanisms have been described for pro-tumorigenic differentiation in cancer, metabolic switches to program the anti-tumorigenic property of TAMs are elusive. MATERIALS AND METHODS: From an unbiased analysis of single-cell transcriptome data from multiple tumor models, we discovered that anti-tumorigenic TAMs uniquely express elevated levels of a specific fatty acid receptor, G-protein-coupled receptor 84 (GPR84). Genetic ablation of GPR84 in mice leads to impaired pro-inflammatory polarization of macrophages, while enhancing their anti-inflammatory phenotype. By contrast, GPR84 activation by its agonist, 6-n-octylaminouracil (6-OAU), potentiates pro-inflammatory phenotype via the enhanced STAT1 pathway. Moreover, 6-OAU treatment significantly retards tumor growth and increases the anti-tumor efficacy of anti-PD-1 therapy. CONCLUSION: Overall, we report a previously unappreciated fatty acid receptor, GPR84, that serves as an important metabolic sensing switch for orchestrating anti-tumorigenic macrophage polarization. Pharmacological agonists of GPR84 hold promise to reshape and reverse the immunosuppressive TME, and thereby restore responsiveness of cancer to overcome resistance to immune checkpoint blockade.","journal":"Cancer Immunology Immunotherapy","year":2024,"id":436188,"datarank":0.37273599746820013,"base_score":2.4849066497880004,"endowment":2.4849066497880004,"self_citation_contribution":0.37273599746820013,"citation_network_contribution":0.0,"self_endowment_contribution":0.37273599746820013,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":235824,"name":"Anjun Ma","orcid":"0000-0001-6269-398X","position":1,"is_corresponding":false},{"id":670482,"name":"Ruohan Zhang","orcid":"0000-0002-7099-7067","position":2,"is_corresponding":false},{"id":39928,"name":"Chen Yao","orcid":"0000-0001-6852-5661","position":3,"is_corresponding":false},{"id":318815,"name":"Chelsea Bolyard","orcid":null,"position":4,"is_corresponding":false},{"id":902026,"name":"Bao Zhao","orcid":"0000-0003-3599-1230","position":5,"is_corresponding":false},{"id":257822,"name":"Cankun Wang","orcid":"0000-0002-0225-9855","position":6,"is_corresponding":false},{"id":1244713,"name":"Thera Pich","orcid":null,"position":7,"is_corresponding":false},{"id":1112463,"name":"Wan‐Tong Li","orcid":"0000-0002-1653-3691","position":8,"is_corresponding":false},{"id":313661,"name":"Nuo Sun","orcid":"0000-0001-9829-8172","position":9,"is_corresponding":false},{"id":235827,"name":"Qin Ma","orcid":"0000-0002-3264-8392","position":10,"is_corresponding":false},{"id":515128,"name":"Haitao Wen","orcid":"0000-0002-6363-2748","position":11,"is_corresponding":false},{"id":366108,"name":"Steven K. Clinton","orcid":"0000-0002-2840-5865","position":12,"is_corresponding":false},{"id":417798,"name":"William E. Carson","orcid":"0000-0001-7024-7533","position":13,"is_corresponding":false},{"id":270306,"name":"Zihai Li","orcid":"0000-0003-4603-927X","position":14,"is_corresponding":false},{"id":642775,"name":"Gang Xin","orcid":"0000-0003-1963-505X","position":15,"is_corresponding":false},{"id":1244284,"name":"Jianying Li","orcid":"0009-0006-2600-9603","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:00:12.706156Z","pmid":"38349405","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}