Abstract: Hepatocellular carcinoma (HCC) patients accounts for 85%-90% of all primary liver cancer patients. Surgical treatment methods, represented by resection and liver transplantation, have relatively good efficacy and are currently the preferred treatment approaches for HCC, with a 5-year survival rate of 70%-80% after treatment. However, the high recurrence rate of HCC remains the greatest challenge in current liver cancer treatment. Due to the heterogeneity of HCC, the efficacy of current chemotherapy drugs and multi-kinase inhibitors is limited. It is crucial to explore new therapeutic strategies. The CD39-CD73-adenosine pathway plays a significant regulatory role in the liver microenvironment by converting pro-inflammatory extracellular adenosine triphosphate (eATP) into immunosuppressive adenosine. Targeting key molecules in this pathway for treatment has shown anti-tumor effects. Strategies of targeting the CD39-CD73-adenosine pathway and combined therapeutic strategies based on the CD39-CD73-adenosine pathway might offer more effective treatment options for HCC patients. This article reviews the biological effects and roles of the CD39-CD73-adenosine pathway in the immune regulation of HCC.