Four adenosine receptors (ARs), all coupled to G-proteins, have been identified; A1R, A2AR, A2BR, and A3R (112, 113). While A1, A2A, and A3 are described as high affinity adenosine receptors (EC50 in the range of 0.1–0.7 μM), A2BR is considered as low affinity because it is activated only in the presence of high concentrations of adenosine (EC50 of 15–25 μM), such as may be found in the TME or under other pathological conditions. Upon adenosine binding, these GPCRs induce the replacement of GDP bound by the heterotrimeric G proteins, a class of GTP hydrolases, with GTP thus resulting in the dissociation of the latter into Gα monomers and Gβγ dimers, now free to modulate downstream effectors before their GTP hydrolysis-induced re-association (114).