{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T18:53:15Z","timestamp":1783363995889,"version":"3.54.6"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Gastric cancer (GC) is characterized by highly heterogeneous tumors, whose progression is genetically driven and closely associated with hypoxia and an immunosuppressive tumor microenvironment (TME). Hypoxia accelerates adenosine accumulation, activates the low-affinity Adora2b receptor, weakens antitumor immunity, and promotes metastasis. Adora2b is lowly expressed in normal gastric mucosa. Still, it is significantly upregulated in diseased tissues, where it is widely expressed in various immune cells and the tumor stroma, mediating immune escape, fibrosis, and vascular remodeling. This review summarizes the cell-type-specific signaling mechanisms of Adora2b in the TME (e.g., T cells, macrophages) and, drawing on research in other tumors, proposes mechanistic explanations for its tissue-specific roles. Based on existing evidence, Adora2b regulates epithelial-mesenchymal transition (EMT) in GC cells via the cAMP\/PKA\/Snail pathway, and preclinical studies show that targeting Adora2b reduces the migration and invasion of GC cells. These findings suggest that targeting Adora2b may provide new insights for gastric cancer therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1687675","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:35:01Z","timestamp":1763534101000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Potential of Adora2b as an immunotherapeutic target for gastric cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Jie","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruixin","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijuan","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4012","DOI":"10.3390\/ijms21114012","article-title":"Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies","volume":"21","author":"Machlowska","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.948647","article-title":"Recent progress and future perspectives of immunotherapy in advanced gastric cancer","volume":"13","author":"Jin","year":"2022","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/17474124.2021.1845140","article-title":"A comprehensive update on early gastric cancer: defining terms, etiology, and alarming risk factors","volume":"15","author":"Yang","year":"2021","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.162.6.3607","article-title":"IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation","volume":"162","author":"Xaus","year":"1999","journal-title":"J Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-117044","article-title":"A2B adenosine receptor dampens hypoxia-induced vascular leak","volume":"111","author":"Eckle","year":"2008","journal-title":"Blood"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-2553","article-title":"CD73-dependent adenosine signaling through adora2b drives immunosuppression in ductal pancreatic cancer","volume":"83","author":"Faraoni","year":"2023","journal-title":"Cancer Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-012-0988-7","article-title":"Transcriptional control of adenosine signaling by hypoxia-inducible transcription factors during ischemic or inflammatory disease","volume":"91","author":"Poth","year":"2013","journal-title":"J Mol Med (Berl)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/s41419-020-2403-6","article-title":"CD73 promotes tumor metastasis by modulating RICS\/RhoA signaling and EMT in gastric cancer","volume":"11","author":"Xu","year":"2020","journal-title":"Cell Death Dis"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605251103","article-title":"A2A adenosine receptor protects tumors from antitumor T cells","volume":"103","author":"Ohta","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B11","article-title":"Adenosine: a novel ulcer modulator in stomachs","volume":"80","author":"Cho","year":"1992","journal-title":"Acta Physiol Hung"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00558.x","article-title":"Stimulation of adenosine A(2B) receptors induces interleukin-6 secretion in cardiac fibroblasts via the PKC-delta-P38 signalling pathway","volume":"159","author":"Feng","year":"2010","journal-title":"Br J Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1202947","article-title":"Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4","volume":"332","author":"Qureshi","year":"2011","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","first-page":"4330329","DOI":"10.1155\/2022\/4330329","article-title":"The effects of CD73 on gastrointestinal cancer progression and treatment","volume":"2022","author":"Sun","year":"2022","journal-title":"J Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"103841","DOI":"10.1016\/j.critrevonc.2022.103841","article-title":"Characteristics of gastric cancer around the world","volume":"181","author":"L\u00f3pez","year":"2023","journal-title":"Crit Rev Oncol Hematol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"109365","DOI":"10.1016\/j.cbi.2021.109365","article-title":"Alcohol consumption and risk of stomach cancer: A meta-analysis","volume":"336","author":"Deng","year":"2021","journal-title":"Chem Biol Interact"},{"key":"B17","doi-asserted-by":"publisher","first-page":"4260","DOI":"10.3390\/nu14204260","article-title":"Effect of dietary salt intake on risk of gastric cancer: A systematic review and meta-analysis of case-control studies","volume":"14","author":"Wu","year":"2022","journal-title":"Nutrients"},{"key":"B18","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.cell.2018.03.039","article-title":"Pathogenic germline variants in 10,389 adult cancers","volume":"173","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","first-page":"11","DOI":"10.21147\/j.issn.1000-9604.2021.01.02","article-title":"Changing trends of disease burden of gastric cancer in China from 1990 to 2019 and its predictions: Findings from Global Burden of Disease Study","volume":"33","author":"Zhang","year":"2021","journal-title":"Chin J Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.834934","article-title":"New advances in nano-drug delivery systems: helicobacter pylori and gastric cancer","volume":"12","author":"Zhu","year":"2022","journal-title":"Front Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1186\/s13046-025-03513-5","article-title":"TRIM6 ablation reverses ICB resistance in MSS gastric cancer by unleashing cGAS-STING-dependent antitumor immunity","volume":"44","author":"Niu","year":"2025","journal-title":"J Exp Clin Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.28463","article-title":"First-line sugemalimab plus chemotherapy for advanced gastric cancer: the GEMSTONE-303 randomized clinical trial","volume":"333","author":"Zhang","year":"2025","journal-title":"Jama"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2022-1149","article-title":"A plain language summary of the CheckMate 649 study: nivolumab in combination with chemotherapy compared to chemotherapy alone for untreated advanced or metastatic cancer of the stomach or esophagus","volume":"19","author":"Janjigian","year":"2023","journal-title":"Future Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2503701","article-title":"Perioperative durvalumab in gastric and gastroesophageal junction cancer","volume":"393","author":"Janjigian","year":"2025","journal-title":"N Engl J Med"},{"key":"B25","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1615\/CritRevEukaryotGeneExpr.2024052979","article-title":"PRMT6 promotes the immune evasion of gastric cancer by upregulating ANXA1","volume":"34","author":"Xu","year":"2024","journal-title":"Crit Rev Eukaryot Gene Expr"},{"key":"B26","doi-asserted-by":"publisher","first-page":"15330338221150318","DOI":"10.1177\/15330338221150318","article-title":"Adenosine receptor A2B antagonist inhibits the metastasis of gastric cancer cells and enhances the efficacy of cisplatin","volume":"22","author":"Wang","year":"2023","journal-title":"Technol Cancer Res Treat"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202300898","article-title":"N4-acetylcytidine drives glycolysis addiction in gastric cancer via NAT10\/SEPT9\/HIF-1\u03b1 Positive feedback loop","volume":"10","author":"Yang","year":"2023","journal-title":"Adv Sci (Weinh)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0222-4","article-title":"Targeting CDK7 increases the stability of Snail to promote the dissemination of colorectal cancer","volume":"26","author":"Zhou","year":"2019","journal-title":"Cell Death Differ"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-23-0090","article-title":"MARCH2, a novel oncogene-regulated SNAIL E3 ligase, suppresses triple-negative breast cancer metastases","volume":"4","author":"Ito","year":"2024","journal-title":"Cancer Res Commun"},{"key":"B30","doi-asserted-by":"publisher","first-page":"113002","DOI":"10.1016\/j.intimp.2024.113002","article-title":"CD19(+)CD73(+) B cells infiltration indicates poor prognosis and unfavorable responses to immunotherapy in gastric cancer","volume":"141","author":"Zhang","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00508","article-title":"CD73's potential as an immunotherapy target in gastrointestinal cancers","volume":"11","author":"Harvey","year":"2020","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4093214","DOI":"10.1155\/2019\/4093214","article-title":"Adenosine generated by regulatory T cells induces CD8(+) T cell exhaustion in gastric cancer through A2aR pathway","volume":"2019","author":"Shi","year":"2019","journal-title":"BioMed Res Int"},{"key":"B33","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13045-024-01524-x","article-title":"cAMP-PKA\/EPAC signaling and cancer: the interplay in tumor microenvironment","volume":"17","author":"Zhang","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.849258","article-title":"Purinergic and adenosinergic signaling in pancreatobiliary diseases","volume":"13","author":"Faraoni","year":"2022","journal-title":"Front Physiol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002801","article-title":"ATP release from vascular endothelia occurs across Cx43 hemichannels and is attenuated during hypoxia","volume":"3","author":"Faigle","year":"2008","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1385\/1-59745-113-4:73","article-title":"Nucleotide metabolism and cell-cell interactions","volume":"341","author":"Eltzschig","year":"2006","journal-title":"Methods Mol Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000250174.31269.70","article-title":"ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function","volume":"99","author":"Eltzschig","year":"2006","journal-title":"Circ Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901851","article-title":"SP1-dependent induction of CD39 facilitates hepatic ischemic preconditioning","volume":"184","author":"Hart","year":"2010","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-06-165746","article-title":"Central role of Sp1-regulated CD39 in hypoxia\/ischemia protection","volume":"113","author":"Eltzschig","year":"2009","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-119701","article-title":"Adenosine and inflammation: CD39 and CD73 are critical mediators in LPS-induced PMN trafficking into the lungs","volume":"23","author":"Reutershan","year":"2009","journal-title":"FASEB J"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-103911","article-title":"Role of extracellular nucleotide phosphohydrolysis in intestinal ischemia-reperfusion injury","volume":"22","author":"Hart","year":"2008","journal-title":"FASEB J"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7947com","article-title":"Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury","volume":"21","author":"Grenz","year":"2007","journal-title":"FASEB J"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.690180","article-title":"CD39\/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia\/reperfusion injury","volume":"116","author":"K\u00f6hler","year":"2007","journal-title":"Circulation"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.4049\/jimmunol.1700997","article-title":"Retraction: hypoxia-inducible factor-1\u03b1-dependent protection from intestinal ischemia\/reperfusion injury involves ecto-5'-nucleotidase (CD73) and the A2B adenosine receptor","volume":"199","author":"Hart","year":"2017","journal-title":"J Immunol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1053\/j.gastro.2008.07.064","article-title":"Extracellular adenosine production by ecto-5'-nucleotidase protects during murine hepatic ischemic preconditioning","volume":"135","author":"Hart","year":"2008","journal-title":"Gastroenterology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0037-0","article-title":"Extracellular ATP and P2 purinergic signalling in the tumour microenvironment","volume":"18","author":"Di Virgilio","year":"2018","journal-title":"Nat Rev Cancer"},{"key":"B47","doi-asserted-by":"publisher","first-page":"3837","DOI":"10.3390\/ijms19123837","article-title":"Targeting adenosine receptor signaling in cancer immunotherapy","volume":"19","author":"Sek","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.16.7432","article-title":"Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor","volume":"89","author":"Zhou","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1124\/pr.117.014878","article-title":"The purinergic system as a pharmacological target for the treatment of immune-mediated inflammatory diseases","volume":"71","author":"Antonioli","year":"2019","journal-title":"Pharmacol Rev"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2018.tb00034.x","article-title":"Intestinal nucleoside transporters: function, expression, and regulation","volume":"8","author":"Pastor-Anglada","year":"2018","journal-title":"Compr Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2174\/138945012800564095","article-title":"Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders","volume":"13","author":"Antonioli","year":"2012","journal-title":"Curr Drug Targets"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.70392","article-title":"Vitamin C mediates IGFBP7 to alleviate chronic atrophic gastritis via the HIF-1\u03b1\/VEGF pathway","volume":"29","author":"Cheng","year":"2025","journal-title":"J Cell Mol Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i12.1912","article-title":"Expression and clinical significance of CD73 and hypoxia-inducible factor-1\u03b1 in gastric carcinoma","volume":"19","author":"Lu","year":"2013","journal-title":"World J Gastroenterol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1007\/s11373-004-8177-5","article-title":"Cyclooxygenase-2 increases hypoxia-inducible factor-1 and vascular endothelial growth factor to promote angiogenesis in gastric carcinoma","volume":"12","author":"Huang","year":"2005","journal-title":"J BioMed Sci"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4321\/S1130-01082006000700006","article-title":"Gastric angiogenesis and Helicobacter pylori infection","volume":"98","author":"Pousa","year":"2006","journal-title":"Rev Esp Enferm Dig"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v8.i4.608","article-title":"Effect of jianpiyiwei capsule on gastric precancerous lesions in rats","volume":"8","author":"Shi","year":"2002","journal-title":"World J Gastroenterol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.05.009","article-title":"Bruceine D inhibits HIF-1\u03b1-mediated glucose metabolism in hepatocellular carcinoma by blocking ICAT\/\u03b2-catenin interaction","volume":"11","author":"Huang","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"B58","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1165\/rcmb.2004-0103OC","article-title":"Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts","volume":"32","author":"Zhong","year":"2005","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-6419com","article-title":"HIF-dependent induction of adenosine A2B receptor in hypoxia","volume":"20","author":"Kong","year":"2006","journal-title":"FASEB J"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2025.09.006","article-title":"Resolution of epithelial dysfunction in eosinophilic esophagitis is mediated by an HIF-1\u03b1-CD73-adenosine signaling axis","volume":"19","author":"Kellett","year":"2025","journal-title":"J Allergy Clin Immunol"},{"key":"B61","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1186\/s12957-023-02970-6","article-title":"Integrative analyses identify CD73 as a prognostic biomarker and immunotherapeutic target in intrahepatic cholangiocarcinoma","volume":"21","author":"Sun","year":"2023","journal-title":"World J Surg Oncol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01322","article-title":"Ectonucleotidase-mediated suppression of lupus autoimmunity and vascular dysfunction","volume":"9","author":"Knight","year":"2018","journal-title":"Front Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201243005","article-title":"Beta2-adrenergic receptor signaling in CD4+ Foxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner","volume":"43","author":"Guereschi","year":"2013","journal-title":"Eur J Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.8.4140","article-title":"Adenosine inhibits macrophage colony-stimulating factor-dependent proliferation of macrophages through the induction of p27kip-1 expression","volume":"163","author":"Xaus","year":"1999","journal-title":"J Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2018.51.2.233","article-title":"Structure and function of vascular endothelial growth factor and its receptor system","volume":"51","author":"Park","year":"2018","journal-title":"BMB Rep"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.7150\/jca.62387","article-title":"CD73 is a hypoxia-responsive gene and promotes the Warburg effect of human gastric cancer cells dependent on its enzyme activity","volume":"12","author":"Cao","year":"2021","journal-title":"J Cancer"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006784","article-title":"Selective deletion of the A1 adenosine receptor abolishes heart-rate slowing effects of intravascular adenosine in vivo","volume":"4","author":"Koeppen","year":"2009","journal-title":"PLoS One"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00737","article-title":"Adenosine: direct and indirect actions on gastric acid secretion","volume":"8","author":"Arin","year":"2017","journal-title":"Front Physiol"},{"key":"B69","doi-asserted-by":"publisher","first-page":"3997","DOI":"10.7150\/jca.50743","article-title":"ADORA1 is a diagnostic-related biomarker and correlated with immune infiltrates in papillary thyroid carcinoma","volume":"12","author":"Lin","year":"2021","journal-title":"J Cancer"},{"key":"B70","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.ccell.2020.02.006","article-title":"ADORA1 inhibition promotes tumor immune evasion by regulating the ATF3-PD-L1 axis","volume":"37","author":"Liu","year":"2020","journal-title":"Cancer Cell"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1434118","article-title":"Unlocking the adenosine receptor mechanism of the tumour immune microenvironment","volume":"15","author":"Han","year":"2024","journal-title":"Frontiers in Immunology"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119833","article-title":"Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation","volume":"100","author":"Jin","year":"1997","journal-title":"J Clin Invest"},{"key":"B73","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.canlet.2017.03.026","article-title":"Mast cells are directly activated by contact with cancer cells by a mechanism involving autocrine formation of adenosine and autocrine\/paracrine signaling of the adenosine A3 receptor","volume":"397","author":"Gorzalczany","year":"2017","journal-title":"Cancer Lett"},{"key":"B74","doi-asserted-by":"publisher","first-page":"e139299","DOI":"10.1172\/JCI139299","article-title":"Adenosine A3 agonists reverse neuropathic pain via T cell-mediated production of IL-10","volume":"131","author":"Durante","year":"2021","journal-title":"J Clin Invest"},{"key":"B75","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/1751-2980.12831","article-title":"Activation of adenosine A3 receptor inhibits inflammatory cytokine production in colonic mucosa of patients with ulcerative colitis by down-regulating the nuclear factor-kappa B signaling","volume":"21","author":"Ren","year":"2020","journal-title":"J Dig Dis"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1055\/s-2002-32802","article-title":"Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage","volume":"40","author":"Bilzer","year":"2002","journal-title":"Z Gastroenterol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.22.012703.104731","article-title":"Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors","volume":"22","author":"Sitkovsky","year":"2004","journal-title":"Annu Rev Immunol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(00)00570-0","article-title":"Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells","volume":"61","author":"Fredholm","year":"2001","journal-title":"Biochem Pharmacol"},{"key":"B79","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1016\/j.bbrc.2015.10.062","article-title":"MicroRNA-128b suppresses tumor growth and promotes apoptosis by targeting A2bR in gastric cancer","volume":"467","author":"Wang","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-009-0028-8","article-title":"Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats","volume":"44","author":"Koizumi","year":"2009","journal-title":"J Gastroenterol"},{"key":"B81","doi-asserted-by":"publisher","first-page":"e004592","DOI":"10.1136\/jitc-2022-004592","article-title":"A(2B) adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models","volume":"10","author":"Tay","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2010.05.016","article-title":"The resurgence of A2B adenosine receptor signaling","volume":"1808","author":"Aherne","year":"2011","journal-title":"Biochim Biophys Acta"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0801324","article-title":"Contribution of adenosine A2B receptors to inflammatory parameters of experimental colitis","volume":"182","author":"Frick","year":"2009","journal-title":"J Immunol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2728","article-title":"Adora2b-elicited Per2 stabilization promotes a HIF-dependent metabolic switch crucial for myocardial adaptation to ischemia","volume":"18","author":"Eckle","year":"2012","journal-title":"Nat Med"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.05.049","article-title":"A2B adenosine receptor gene deletion attenuates murine colitis","volume":"135","author":"Kolachala","year":"2008","journal-title":"Gastroenterology"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.227","article-title":"Blockade of adenosine A2B receptors ameliorates murine colitis","volume":"155","author":"Kolachala","year":"2008","journal-title":"Br J Pharmacol"},{"key":"B87","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.immuni.2013.11.020","article-title":"Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation","volume":"40","author":"Campbell","year":"2014","journal-title":"Immunity"},{"key":"B88","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1007\/s12072-019-10003-2","article-title":"Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma","volume":"14","author":"Liao","year":"2020","journal-title":"Hepatol Int"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.663011","article-title":"Expression and gene regulation network of adenosine receptor A2B in lung adenocarcinoma: A potential diagnostic and prognostic biomarker","volume":"8","author":"Sui","year":"2021","journal-title":"Front Mol Biosci"},{"key":"B90","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s13045-022-01359-4","article-title":"Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma","volume":"15","author":"Liu","year":"2022","journal-title":"J Hematol Oncol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.159","article-title":"CD73 regulates anti-inflammatory signaling between apoptotic cells and endotoxin-conditioned tissue macrophages","volume":"24","author":"Murphy","year":"2017","journal-title":"Cell Death Differ"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700850","article-title":"A(2A) adenosine receptor gene deletion or synthetic A(2A) antagonist liberate tumor-reactive CD8(+) T cells from tumor-induced immunosuppression","volume":"201","author":"Kjaergaard","year":"2018","journal-title":"J Immunol"},{"key":"B93","doi-asserted-by":"publisher","first-page":"e004114","DOI":"10.1136\/jitc-2021-004114","article-title":"Genetic characteristics involving the PD-1\/PD-L1\/L2 and CD73\/A2aR axes and the immunosuppressive microenvironment in DLBCL","volume":"10","author":"Zhang","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.2.459","article-title":"CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation","volume":"182","author":"Krummel","year":"1995","journal-title":"J Exp Med"},{"key":"B95","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.intimp.2018.07.023","article-title":"Adenosine signaling: Next checkpoint for gastric cancer immunotherapy","volume":"63","author":"Shi","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2021.08.006","article-title":"Impact of intratumoural CD73 expression on prognosis and therapeutic response in patients with gastric cancer","volume":"157","author":"He","year":"2021","journal-title":"Eur J Cancer"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1163585","article-title":"The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer","volume":"14","author":"Strickland","year":"2023","journal-title":"Front Immunol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"104130","DOI":"10.1016\/j.jri.2023.104130","article-title":"The immune checkpoint protein PD-1: Its emerging regulatory role in memory T cells","volume":"159","author":"Lin","year":"2023","journal-title":"J Reprod Immunol"},{"key":"B99","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1186\/s12943-022-01645-2","article-title":"The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies","volume":"21","author":"Bai","year":"2022","journal-title":"Mol Cancer"},{"key":"B100","doi-asserted-by":"publisher","first-page":"995","DOI":"10.20892\/j.issn.2095-3941.2024.0228","article-title":"Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy","volume":"21","author":"Yang","year":"2024","journal-title":"Cancer Biol Med"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.11729","article-title":"Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression","volume":"7","author":"Sorrentino","year":"2016","journal-title":"Oncotarget"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0252424","article-title":"Adenosine\/TGF\u03b2 axis in regulation of mammary fibroblast functions","volume":"16","author":"Vasiukov","year":"2021","journal-title":"PLoS One"},{"key":"B103","doi-asserted-by":"publisher","first-page":"4411","DOI":"10.3390\/ijms20184411","article-title":"Vascular endothelial cell biology: an update","volume":"20","author":"Kr\u00fcger-Genge","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B104","doi-asserted-by":"publisher","first-page":"198","DOI":"10.4049\/jimmunol.1101845","article-title":"Adenosine A2B receptor blockade slows growth of bladder and breast tumors","volume":"188","author":"Cekic","year":"2012","journal-title":"J Immunol"},{"key":"B105","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1158\/2326-6066.CIR-22-0260","article-title":"CD73 inhibits cGAS-STING and cooperates with CD39 to promote pancreatic cancer","volume":"11","author":"Jacoberger-Foissac","year":"2023","journal-title":"Cancer Immunol Res"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-1690","article-title":"At the interface of tumor-associated macrophages and fibroblasts: immune-suppressive networks and emerging exploitable targets","volume":"30","author":"Timperi","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1097\/MOG.0000000000000392","article-title":"Physiologic, pathophysiologic, and pharmacologic regulation of gastric acid secretion","volume":"33","author":"Schubert","year":"2017","journal-title":"Curr Opin Gastroenterol"},{"key":"B108","article-title":"Biochemistry, protein catabolism","volume-title":"StatPearls","author":"Gurina","year":"2025"},{"key":"B109","doi-asserted-by":"publisher","first-page":"625","DOI":"10.3390\/molecules22040625","article-title":"Expression of adenosine A(2B) receptor and adenosine deaminase in rabbit gastric mucosa ECL cells","volume":"22","author":"Arin","year":"2017","journal-title":"Molecules"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.2174\/1381612823666170616080517","article-title":"Membrane-bound ATP-dependent energy systems, as extra- and intracellular key signals for gastrointestinal functions and their regulations in the gastrointestinal mucosa","volume":"23","author":"Mozsik","year":"2017","journal-title":"Curr Pharm Des"},{"key":"B111","doi-asserted-by":"publisher","first-page":"e21004","DOI":"10.1016\/j.heliyon.2023.e21004","article-title":"A2BR facilitates the pathogenesis of H. pylori-associated GU by inducing oxidative stress through p38 MAPK phosphorylation","volume":"9","author":"Tang","year":"2023","journal-title":"Heliyon"},{"key":"B112","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.3390\/ijms26031156","article-title":"Immune cell interactions and immune checkpoints in the tumor microenvironment of gastric cancer","volume":"26","author":"Cozac-Sz\u0151ke","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B113","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1161\/ATVBAHA.119.313002","article-title":"CD73 promotes age-dependent accretion of atherosclerosis","volume":"40","author":"Sutton","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.10.013","article-title":"CCR6 signaling inhibits suppressor function of induced-Treg during gut inflammation","volume":"88","author":"Kulkarni","year":"2018","journal-title":"J Autoimmun"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-320368","article-title":"Dissecting transcriptional heterogeneity in primary gastric adenocarcinoma by single cell RNA sequencing","volume":"70","author":"Zhang","year":"2021","journal-title":"Gut"},{"key":"B116","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s13073-017-0484-3","article-title":"Actionable gene-based classification toward precision medicine in gastric cancer","volume":"9","author":"Ichikawa","year":"2017","journal-title":"Genome Med"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-0545","article-title":"Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs","volume":"19","author":"Allard","year":"2013","journal-title":"Clin Cancer Res"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1007\/s11427-023-2459-8","article-title":"Structural insight into the dual-antagonistic mechanism of AB928 on adenosine A(2) receptors","volume":"67","author":"Weng","year":"2024","journal-title":"Sci China Life Sci"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1039\/D5RA02235E","article-title":"Therapeutic potential of adenosine receptor modulators in cancer treatment","volume":"15","author":"Maity","year":"2025","journal-title":"RSC Adv"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.3233\/CBM-201621","article-title":"LncRNA-SNHG7 interferes with miR-34a to de-sensitize gastric cancer cells to cisplatin","volume":"30","author":"Pei","year":"2021","journal-title":"Cancer biomark"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2019.37.15_suppl.2604","article-title":"AB928, a novel dual adenosine receptor antagonist, combined with chemotherapy or AB122 (anti-PD-1) in patients (pts) with advanced tumors: Preliminary results from ongoing phase I studies","volume":"37","author":"Biosciences","year":"2019","journal-title":"J Clin Oncol"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1080\/21655979.2021.1953217","article-title":"Hypoxia-inducible factor-1alpha protects the liver against ischemia-reperfusion injury by regulating the A2B adenosine receptor","volume":"12","author":"Zhang","year":"2021","journal-title":"Bioengineered"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1687675\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T06:35:03Z","timestamp":1763534103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1687675\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":122,"alternative-id":["10.3389\/fimmu.2025.1687675"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1687675","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]},"article-number":"1687675"}}