Advances in CD73 inhibitors for immunotherapy: Antibodies, synthetic small molecule compounds, and natural compounds

Tumors, a disease with a high mortality rate worldwide, have become a serious threat to human health. Exonucleotide-5′-nucleotidase (CD73) is an emerging target for tumor therapy. Its inhibition can significantly reduce adenosine levels in the tumor microenvironment. It has a better therapeutic effect on adenosine-induced immunosuppression. In the immune response, extracellular ATP exerts immune efficacy by activating T cells. However, dead tumor cells release excess ATP, overexpress CD39 and CD73 on the cell membrane and catabolize this ATP to adenosine. This leads to further immunosuppression. There are a number of inhibitors of CD73 currently under investigation. These include antibodies, synthetic small molecule inhibitors and a number of natural compounds with prominent roles in the anti-tumor field. However, only a small proportion of the CD73 inhibitors studied to date have successfully reached the clinical stage. Therefore, effective and safe inhibition of CD73 in oncology therapy still holds great therapeutic potential. This review summarizes the currently reported CD73 inhibitors, describes their inhibitory effects and pharmacological mechanisms, and provides a brief review of them. It aims to provide more information for further research and development of CD73 inhibitors.