{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:10:54Z","timestamp":1785420654100,"version":"3.56.0"},"reference-count":154,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"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>The therapeutic landscape of advanced melanoma has been transformed by immune checkpoint inhibitors (ICIs); however, primary and acquired resistance remain formidable challenges for a substantial subset of patients. Emerging evidence identifies the CD73-adenosine axis as a critical \u201cmetabolic immune checkpoint\u201d that orchestrates an immunosuppressive tumor microenvironment (TME). This review systematically explores the biochemical cascade in which extracellular ATP is converted into immunosuppressive adenosine by the sequential action of ectonucleotidases CD39 and CD73. We detail the multidimensional regulation of CD73 expression, driven by a convergence of environmental stressors such as hypoxia-stabilized HIF-1\u03b1, oncogenic MAPK signaling, and pro-inflammatory cytokines including TGF-\u03b2 and TNF-\u03b1. Furthermore, we evaluate the clinical utility of CD73 as a prognostic and predictive biomarker, highlighting the dichotomous significance of its expression on tumor versus immune cells and the potential of liquid biopsy-based monitoring via soluble CD73 activity and melanoma-derived exosomes (MTEX). Finally, we discuss therapeutic strategies to dismantle this metabolic barrier, ranging from monoclonal antibodies and small-molecule inhibitors to synergistic combinations with ICIs, targeted therapies, and next-generation cellular engineering utilizing CRISPR\/Cas9-mediated gene editing. Integrating adenosinergic blockade into the framework of precision immuno-oncology represents a pivotal dimension in overcoming treatment resistance and improving clinical outcomes for patients with melanoma.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1839832","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:27:20Z","timestamp":1785418040000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The CD73-adenosine axis in melanoma: from multidimensional regulation to precision immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoting","family":"Liu","sequence":"first","affiliation":[{"name":"Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University","place":["Huzhou, China"]},{"name":"Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Chen","sequence":"additional","affiliation":[{"name":"Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University","place":["Huzhou, China"]},{"name":"Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Dermatology, First Affiliated Hospital of Huzhou University","place":["Huzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.soc.2010.09.007","article-title":"Staging and prognosis of cutaneous melanoma","volume":"20","author":"Dickson","year":"2011","journal-title":"Surg Oncol Clin N Am"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31551","article-title":"Annual report to the nation on the status of cancer, part I: National cancer statistics","volume":"124","author":"Cronin","year":"2018","journal-title":"Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1503093","article-title":"Pembrolizumab versus ipilimumab in advanced 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