Inhibitors of Ectonucleotidase CD39 for Immunotherapy of Cancer and Infections─Recent Developments and Future Perspectives

Ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39) is a purinergic immune checkpoint protein and a potential biomarker in tumor immunotherapy. The enzyme can hydrolyze extracellular adenosine tri- and diphosphate (ATP, ADP) to generate adenosine monophosphate (AMP), which is subsequently hydrolyzed by ecto-5'-nucleotidase (CD73) to generate immunosuppressive adenosine (ADO). CD39 inhibition increases the extracellular concentration of immunostimulatory ATP, concomitantly reducing ADO production. In the tumor microenvironment, ATP can recruit a variety of antitumor immune cells, including T cells, dendritic cells, M1 macrophages, B cells, natural killer cells, and N1 neutrophils, to the tumor site, thereby suppressing various tumor activities. Here, we present non-nucleotidic and nucleotide-derived CD39 inhibitors, structural insights, current clinical studies, and strategies for combination therapy. We highlight the potential advantages of targeting CD39 in tumor immunotherapy and provide valuable insights to guide future drug development and therapeutic applications.