Adora2b, an adenosine receptor, is a key component in the adenosine signaling pathway. Among the four adenosine receptors (Adora1, Adora2a, Adora2b, Adora3), Adora2b has the lowest affinity for adenosine. It is present in normal pancreas tissue, and its levels increase in injured or diseased pancreatic tissue. Adora2b is expressed on many immune cells, and its activation can lead to reduced adaptive anti-tumor response and immune suppression. It is also involved in processes like fibrosis, perineural invasion, and vascular changes in the tumor microenvironment. Additionally, it has been associated with inflammation regulation and tissue protection in hypoxic or inflammatory conditions [1,2].

In pancreatic ductal adenocarcinoma (PDAC), Adora2b is a determinant of adenosine-mediated immunosuppression. Delivery of CD73 small-molecule inhibitors, which affects adenosine generation, reduced tumor development in mouse models, indicating the importance of Adora2b-related adenosine signaling in PDAC growth [3]. In myocardial ischemia and reperfusion injury, targeting the myocardial equilibrative nucleoside transporter ENT1 increased cardiac adenosine signaling and provided cardioprotection, with Adora2b signaling on myeloid-inflammatory cells being implicated in this protection [4].

In summary, Adora2b plays crucial roles in immune regulation, especially in the context of tumor-associated immunosuppression, and in tissue protection during ischemia-reperfusion injury. Gene-knockout or conditional-knockout mouse models have been instrumental in revealing these functions, highlighting its potential as a therapeutic target in diseases like PDAC and for cardioprotection.