{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T06:27:06Z","timestamp":1786688826196,"version":"build-2736575974"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors have improved outcomes for a subset of patients with non-small cell lung cancer (NSCLC), but the immunosuppressive tumor microenvironment (TME) limits their efficacy. Polarization of tumor-associated macrophages (TAMs) toward an M2 phenotype is a key feature of immune escape in NSCLC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Using the CD73 (NT5E)-mediated adenosine metabolic pathway as an entry point, to elucidate its role and molecular mechanisms in driving immunosuppressive TAM polarization in NSCLC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using TCGA datasets and clinical tissue samples, we analyzed correlations between CD73 expression, macrophage infiltration, and patient prognosis. NSCLC cell lines were used to establish CD73 knockdown\/overexpression and pharmacological inhibition models and to quantify extracellular adenosine generation. Tumor cell-conditioned media and Transwell co-culture systems were constructed to induce THP-1 macrophage polarization. Flow cytometry, qPCR, and ELISA were used to assess M1\/M2 markers and cytokine profiles. Rescue experiments were performed by supplementing exogenous adenosine or 5\u2019-N-ethylcarboxamidoadenosine (NECA), and adenosine dependence was validated using an A2A receptor antagonist together with downstream cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling measurements.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      TCGA-based and clinical-sample analyses suggested that high CD73 expression was associated with poorer prognosis and increased infiltration of M2-like macrophages.\n                      <jats:italic>In vitro<\/jats:italic>\n                      experiments confirmed that CD73 expression in NSCLC cells correlated positively with extracellular adenosine production. Pharmacological inhibition or knockdown of CD73 significantly reduced adenosine levels and weakened tumor-derived induction of macrophage M2 polarization, manifested as downregulation of M2 markers with enhancement of the M1 phenotype. Exogenous adenosine supplementation restored M2 polarization, whereas blockade of the A2A receptor or inhibition of the PKA\/CREB pathway reversed this polarization effect and attenuated downstream CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell dysfunction-associated changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      CD73-driven adenosine signaling promotes immunosuppressive M2 polarization of NSCLC-associated macrophages through the adenosine-A2A receptor (A2AR)-cAMP\/PKA\/CREB signaling axis, providing\n                      <jats:italic>in vitro<\/jats:italic>\n                      mechanistic evidence supporting CD73 targeting to improve the tumor immune microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1875070","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T05:32:39Z","timestamp":1786685559000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular mechanisms by which tumor cell CD73-mediated adenosine signaling drives M2 polarization of macrophages in non-small cell lung cancer"],"prefix":"10.3389","volume":"14","author":[{"given":"Qi","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binbin","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingdong","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, Shanghai Second People\u2019s Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1111\/imr.12528","article-title":"The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets","volume":"276","author":"Allard","year":"2017","journal-title":"Immunol. 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