Adenosine is a key metabolic and immune-checkpoint regulator implicated in the tumor escape from the host

immune system. Major gaps in knowledge that impede the development of effective adenosine-based ther-

apeutics include: (1) lack of consideration of redundant pathways controlling ATP and adenosine levels; (2)

lack of distinction between receptor-dependent and -independent effects of adenosine, and (3) focus on

extracellular adenosine without consideration of intracellular metabolism and compartmentalization. In light

of current clinical trials, we provide an overview of adenosine metabolism and point out the need for a more

careful evaluation of the entire purinome in emerging cancer therapies.