CD39 and CD73: biological functions, diseases and therapy

Abstract Cluster of differentiation 39 (CD39) and CD73 are ectonucleotidases that play pivotal roles in purinergic signaling. CD39 catalyzes the hydrolysis of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and subsequently to adenosine monophosphate (AMP), while CD73 further catalyzes the hydrolysis of AMP to adenosine. These ectonucleotidases are expressed across diverse cell types and exhibit pleiotropic functions in immune regulation, physiological homeostasis, and disease pathogenesis. Recent preclinical studies have increasingly identified CD39 and CD73 as promising therapeutic targets in various disease states, particularly in cancer. This review provides a comprehensive summary of the current advancements in CD39 and CD73 research, emphasizing their structural characteristics, distribution, enzymatic and non-enzymatic activities, as well as their biological functions. We discuss the involvement of CD39 and CD73 in multiple disease states, including cancer, autoimmune disorders, inflammatory diseases, cardiovascular disorders, infectious diseases, and neurological disorders. Furthermore, we present existing preclinical and clinical research on reported CD39 and CD73 inhibitors, which include small-molecule inhibitors, antibodies, advanced delivery systems, and combinations with adenosine receptor antagonists, targeted therapy, immunotherapy, and chemotherapy, thereby providing a foundation for future investigations. The anti-tumor efficacy of these inhibitors, observed across various tumor types, is primarily mediated through adenosine-dependent mechanisms. Despite these encouraging preclinical findings, several challenges hinder the application of CD39 and CD73 inhibitors. It is essential to optimize and modify their structures, enhance dosage forms, and adjust both the dosage and timing of administration to achieve high selectivity while minimizing off-target effects. Future research is anticipated to concentrate on mechanistic exploration and rational drug design, while also broadening their therapeutic potential to encompass additional diseases.