The CD73-adenosine axis in melanoma: from multidimensional regulation to precision immunotherapy

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 "metabolic immune checkpoint" 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-1α, oncogenic MAPK signaling, and pro-inflammatory cytokines including TGF-β and TNF-α. 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.