{"doi":"10.1371/journal.pbio.3000687","title":"IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival","abstract":"In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.","journal":"PLoS Biology","year":2020,"id":53161,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":121,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":270664,"name":"Jeffrey J. Rodvold","orcid":"0000-0002-4873-210X","position":1,"is_corresponding":false},{"id":270665,"name":"Xian Su","orcid":"0000-0002-8295-876X","position":2,"is_corresponding":false},{"id":272767,"name":"Stephen Searles","orcid":null,"position":3,"is_corresponding":false},{"id":272768,"name":"Alyssa Lew","orcid":null,"position":4,"is_corresponding":false},{"id":270666,"name":"Takao Iwawaki","orcid":"0000-0001-8753-1979","position":5,"is_corresponding":false},{"id":270667,"name":"Gonzalo Almanza","orcid":"0009-0004-7204-6777","position":6,"is_corresponding":false},{"id":270668,"name":"T. Cameron Waller","orcid":"0000-0002-0313-6646","position":7,"is_corresponding":false},{"id":270669,"name":"Jonathan H. Lin","orcid":"0000-0002-7438-6941","position":8,"is_corresponding":false},{"id":270670,"name":"Kristen Jepsen","orcid":"0000-0002-2874-0823","position":9,"is_corresponding":false},{"id":2188,"name":"Hannah Carter","orcid":"0000-0002-1729-2463","position":10,"is_corresponding":false},{"id":262935,"name":"Maurizio Zanetti","orcid":"0000-0001-6346-8776","position":11,"is_corresponding":false},{"id":272766,"name":"Alyssa Batista","orcid":null,"position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-18T20:44:25.349797Z","pmid":"32520957","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":[]}