6.Conclusion
In recent years, therapeutic advances in cancer immunotherapy (CIT) have emerged rapidly, reflecting the importance of human immune system interactions with cancer, as well as the complex and highly regulated nature of the immune system[70, 71]. Under the background of complex immune network, point-to-point therapy has been unable to achieve satisfactory tumor treatment effect, so combining various targeting axes or immune checkpoints will become a new direction of tumor treatment.
Adenosine axis’s role in tumor microenvironment is mainly induced by hypoxia, so some studies have also called it hypoxia-adenosine axis. Extracellular adenosine increases in hypoxic conditions, and simultaneously the expression of CD39 and CD73 improves simultaneously[7]. Antihypoxia-adenosine therapy is synergistic with other immune checkpoint inhibitors, such as CTLA-4 mAb and PD-1 mAb. The combination of anti-hypoxia-adenosine strategies may enhance clinical response to other immunotherapies and chemotherapy and radiotherapy[67].With advances in the treatment of tumors with immune checkpoint blockers such as CTLA-4 and PD-1/PDL1, more therapeutic targets have been sought, including but not limited to the immune targets in the adenosine energy axis mentioned above, in order to overcome the problems of incomplete tumor regression or recurrence after treatment[3].More identified immune checkpoint suppressor molecules are emerging as new potential targets for tumor therapy. In the TME, these molecular mechanisms may operate and may be supplementary to immunotherapies that had been approved [22, 72, 73].When immune escape of tumor cells becomes a difficult problem to conquer tumors[74],the use of these immune checkpoint inhibitors can offset immune escape of tumor cells to a certain extent and further improve the response rate. Without increasing or even decreasing the adverse events related to excessive damage of tissue, autoimmunity, and other immune-associated side reactions associated with the use of immune checkpoint inhibitors alone[18, 75-77].In the future, the treatment trend of malignant tumors will be developed from point-to-point therapy targeting individual immune checkpoints to the combination of immune networks composed of various signaling pathways, such as adenosine axis. Even therapies that are not traditionally considered immunotherapies can induce or enhance antitumor immunity. As a result, they may force tumors to upregulate immune checkpoints ,which can be blocked as part of a combined strategy[76, 78-81].
7. Acknowledgments
This work was supported by the National Natural Science Foundation of China Youth Project (grant no. 81900131), the National Natural Science Foundation of China Youth Project (grant no. 8210010129), the Tianjin Municipal Natural Science Foundation (grant no. 18JCQNJC80400), the Tianjin Education Commission Research Project (grant no. 2018KJ043), the Tianjin Education Commission Research Project (grant no. 2018KJ045), and the Tianjin Science and Technology Planning Project (no. 20YFZCSY00060).Tianjin Municipal Health Commission Youth Project(grant no. TJWJ2021QN001);Medjaden Academy & Research Foundation for Young Scientists (Grant No. MJR20221011);Tianjin Key Medical Discipline(Specialty) Construction project.