{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Scolaro T"],"funding":["European Research Council","NIDDK NIH HHS","European Molecular Biology Organization (EMBO)","Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)","NIH HHS","Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)"],"pagination":["1206-1226"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11358017"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["5(8)"],"pubmed_abstract":["Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y<sub>6</sub>. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y<sub>6</sub> in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in "],"journal":["Nature cancer"],"pubmed_title":["Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance."],"pmcid":["PMC11358017"],"funding_grant_id":["G0B4620N","OT2 OD030544","U2C DK119886","28245","ImmunoFit, 773208","G0A7419N","11M9922N","SEG9251","773208"],"pubmed_authors":["Tzoumpa A","Mazzone M","Van Acker HH","Van Haele M","Fendt SM","Carmeliet P","Trotta R","Scolaro T","Varamo C","Naulaerts S","Ferreira Campos AM","Shirgaonkar N","Di Matteo M","Wang L","Topal B","Amorim R","Manco M","Radenkovic S","Beatovic A","Daniluk J","Fernandez Garcia J","Antoranz A","Voets T","Goveia J","Wang Y","Sargsian A","Prenen F","Garg AD","Rouhi P","Ponti D","Manshian B","Soenen S","Ghesquiere B","DasGupta R","Pecqueux M","Berardi E","Doglioni G","Roskams T"],"additional_accession":[]},"is_claimable":false,"name":"Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.","description":"Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y<sub>6</sub>. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y<sub>6</sub> in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in ","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Aug","modification":"2026-06-01T19:37:20.063Z","creation":"2025-04-07T12:29:38.635Z"},"accession":"S-EPMC11358017","cross_references":{"pubmed":["38844817"],"doi":["10.1038/s43018-024-00771-8"]}}