The CD39-CD73-adenosine axis: Master regulator of immune evasion and therapeutic target in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) exhibits persistent resistance to immunotherapy, with a 5-year survival rate around 10 %. The CD39-CD73-adenosine axis emerges as a critical mediator of immune evasion in PDAC, generating pathologically elevated adenosine concentrations that systematically suppress anti-tumor immunity. This purinergic pathway operates through sequential ATP hydrolysis by CD39 and CD73 ectonucleotidases, producing adenosine that engages four G-protein-coupled receptors (A1, A2A, A2B, A3) to orchestrate comprehensive immunosuppression. A2A and A2B receptors mediate the predominant immunosuppressive effects through cAMP-PKA signaling, inhibiting CD8+ T cell and NK cell cytotoxicity while enhancing regulatory T cells, myeloid-derived suppressor cells, and M2-like tumor-associated macrophages. Cancer-associated fibroblasts and tumor cells contribute to adenosine production and respond to its signaling, establishing self-reinforcing immunosuppressive networks. Current therapeutic strategies demonstrate promising early clinical results, with multiple CD73 inhibitors, CD39 antagonists, and adenosine receptor antagonists under evaluation in PDAC trials. However, critical challenges remain: CD73's non-enzymatic functions promote chemoresistance independently of adenosine production, explaining why enzymatic inhibitors fail to enhance chemotherapy sensitivity. The spatial adenosine gradient within tumors, receptor-specific paradoxical effects, and compensatory resistance mechanisms through AMP accumulation further complicate therapeutic targeting. Multi-targeted approaches combining adenosine pathway inhibition with checkpoint blockade, chemotherapy, and stromal modulation show enhanced efficacy. Future directions include developing predictive biomarker panels, optimizing combination sequences, and designing inhibitors targeting both enzymatic and structural functions of purinergic enzymes. Understanding these complex interactions provides the foundation for transforming the adenosine pathway from an immunosuppressive barrier into a therapeutic opportunity in PDAC.