Abstract CD39 plays a pivotal role in the ATP-to-adenosine signalling pathway, serving as a critical mediator of immune suppression within the tumour microenvironment. Increasing preclinical evidence indicates that its inhibition can restore antitumour immunity and improve the efficacy of established treatments. In this review, we summarise the biology of CD39, its role in shaping the immunosuppressive tumour microenvironment, and therapeutic strategies currently under development. We also discuss early clinical progress and safety considerations, along with major challenges and future perspectives. Targeting CD39 represents a promising strategy to overcome tumour-induced immunosuppression and ongoing advances in therapeutic development could usher in next-generation immunotherapies.