{"doi":"10.1038/s41586-024-08290-3","title":"Evolution of myeloid-mediated immunotherapy resistance in prostate cancer","abstract":"Abstract Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs) 1,2 , partly because there are immunosuppressive myeloid cells in tumours 3,4 . However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts ( SPP1 hi -TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8 + T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1 hi -TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1 hi -TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1 hi -TAM-mediated immunosuppression in CD8 + T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1 hi -TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1 hi -TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.","journal":"Nature","year":2024,"id":416381,"datarank":2.1834035700573087,"base_score":5.043425116919247,"endowment":5.043425116919247,"self_citation_contribution":0.7565137675378871,"citation_network_contribution":1.4268898025194214,"self_endowment_contribution":0.7565137675378871,"citer_contribution":1.4268898025194214,"corpus_percentile":null,"corpus_rank":null,"citation_count":154,"citer_count":100,"citers_with_citation_signal":80,"citers_with_endowment":80,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE274229"]},"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":818188,"name":"Zenghua Fan","orcid":"0000-0002-7309-8331","position":1,"is_corresponding":false},{"id":624162,"name":"Matthew Clark","orcid":"0000-0003-0355-2516","position":2,"is_corresponding":false},{"id":1200629,"name":"Averey Lea","orcid":null,"position":3,"is_corresponding":false},{"id":771560,"name":"Diamond Luong","orcid":"0000-0001-6832-5408","position":4,"is_corresponding":false},{"id":1200630,"name":"Ali Setayesh","orcid":null,"position":5,"is_corresponding":false},{"id":574745,"name":"Alec Starzinski","orcid":"0000-0001-5266-9660","position":6,"is_corresponding":false},{"id":1200631,"name":"Rachel Wolters","orcid":null,"position":7,"is_corresponding":false},{"id":1022508,"name":"Marcel Arias-Badia","orcid":"0000-0003-2270-0676","position":8,"is_corresponding":false},{"id":650426,"name":"Kate Allaire","orcid":null,"position":9,"is_corresponding":false},{"id":81062,"name":"Kaichun Wu","orcid":"0000-0002-0699-9666","position":10,"is_corresponding":false},{"id":1200632,"name":"Vibha Gurunathan","orcid":null,"position":11,"is_corresponding":false},{"id":1200633,"name":"Laura Valderrábano","orcid":null,"position":12,"is_corresponding":false},{"id":567168,"name":"Xiao X. Wei","orcid":"0000-0001-7093-0383","position":13,"is_corresponding":false},{"id":1199612,"name":"Richard A. Miller","orcid":"0000-0002-5696-2503","position":14,"is_corresponding":false},{"id":418,"name":"Eliezer M. Van Allen","orcid":"0000-0002-0201-4444","position":15,"is_corresponding":false},{"id":24099,"name":"Lawrence Fong","orcid":"0000-0002-6428-428X","position":16,"is_corresponding":false},{"id":1199611,"name":"Aram Lyu","orcid":"0000-0003-3044-4887","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T01:56:20.964471Z","pmid":"39633050","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":[]}