REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Enzymatic and Microenvironmental Regulation in Adenosine Metabolism-Mediated Immunosuppression
Provisionally accepted
- 1Minjiang University, Fuzhou, China
- 2Hubei University of Chinese Medicine, Wuhan, China
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Adenosine (ADO), as an endogenous purine nucleoside, can regulate almost all aspects of tissue function. However, its abnormal accumulation in the tumor microenvironment (TME) induces immune tolerance and promotes tumor immune evasion by activating adenosine receptors (ADOR). Regulating ADO metabolism in the TME holds promise for ameliorating ADO-mediated immunosuppression and restoring antitumor immune responses. Extensive research has highlighted the pivotal role of ADO in tumor immune suppression and preclinical development of inhibitors targeting ADOR. However, systematic integration in ADO metabolism of microenvironmental influences, enzyme and protein regulation, and targeted intervention strategies through multiple pathways remain insufficient. This review systematically summarizes the key aspects of targeting ADO-mediated immunosuppression, including the feature of TME, enzymes involved in ADO metabolism (e.g., CD39/CD73/ADK/ADA), and ADOR interventions. Additionally, the necessity of comprehensively regulating ADO metabolism and the immune microenvironment through multi-level coordinated interventions is also explored, as well as the latest combined regulatory strategies. Moreover, the major challenges in current research on ADO metabolic regulation are also critically analyzed and the future research directions are proposed to address the dual challenges of ADO metabolic diversity and TME complexity, aiming to develop more precise and effective immunotherapeutic strategies.
Keywords: adenosine metabolism, coordinated intervention, Enzymatic regulation, Immunosuppression, Tumor Microenvironment
Received: 05 Nov 2025; Accepted: 15 Dec 2025.
Copyright: © 2025 LI, Chen, Li, LIANG and Lou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: LING LIANG
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