{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T05:04:40Z","timestamp":1789362280945,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Adenosine accumulation within the tumour microenvironment is a major barrier to effective cancer immunotherapy, driving potent immunosuppression through adenosine receptor signalling. While current clinical strategies primarily target the A\n                    <jats:sub>2A<\/jats:sub>\n                    adenosine receptor, emerging evidence suggests that adenosine-mediated immune regulation, particularly in human myeloid cells such as macrophages, involves coordinated signalling through both A\n                    <jats:sub>2A<\/jats:sub>\n                    and A\n                    <jats:sub>2B<\/jats:sub>\n                    receptors. In this study, we define for the first time the adenosine receptor pathways responsible for the immunosuppressive effects of the adenosine analogue 5\u2032-N-Ethylcarboxamidoadenosine (NECA) in human monocyte-derived macrophages and determine the downstream consequences for T cell function. NECA-conditioned macrophages acquired an immunosuppressive, M2-like phenotype, characterised by reduced production of pro-inflammatory cytokines (IL-12, IL-23, IL-6, TNF\u03b1) and increased expression of VEGF-A and IL-10. Functionally, these macrophages impaired T cell effector responses, markedly reducing Th1-type responses as indicated by ablation of IFN\u03b3 production. Importantly, reversal of macrophage polarisation and restoration of T cell function could be achieved by simultaneous blockade of both A\n                    <jats:sub>2A<\/jats:sub>\n                    and A\n                    <jats:sub>2B<\/jats:sub>\n                    receptors. These findings identify the potential of simultaneously inhibiting the A\n                    <jats:sub>2A<\/jats:sub>\n                    and A\n                    <jats:sub>2B<\/jats:sub>\n                    receptors as a novel key strategy for overcoming adenosine-driven immunosuppression and enhancing the efficacy of cancer immunotherapies targeting the tumour microenvironment.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1845291","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T04:35:56Z","timestamp":1789360556000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual blockade of adenosine A2A and A2B receptors is required to reverse NECA-induced immunosuppression in human macrophages: Implications for cancer immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Foteini","family":"Patera","sequence":"first","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]},{"name":"University of Nottingham and University of Birmingham Centre of Membrane Proteins and Receptors","place":["The Midlands, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meryem","family":"Gultekin","sequence":"additional","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Malecka","sequence":"additional","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]},{"name":"School of Veterinary Medicine and Science, University of Nottingham","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryony","family":"Heath","sequence":"additional","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tajkia","family":"Musarrat","sequence":"additional","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aanchal Preet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poulam M.","family":"Patel","sequence":"additional","affiliation":[{"name":"Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Science Road, University Park","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Hill","sequence":"additional","affiliation":[{"name":"University of Nottingham and University of Birmingham Centre of Membrane Proteins and Receptors","place":["The Midlands, United Kingdom"]},{"name":"Division of Physiology, Pharmacology and Neuroscience. 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