Since multiple ecto-enzymes with redundant functions contribute toward extracellular adenosine production and both A2AR and A2BR triggering mediate the majority of adenosine's pro-tumoral effects, monotherapies may not be sufficient to block the adenosine-signaling axis. In addition, there is strong rationale for combination with IMTs, such as ICB of PD-1/PDL-1 or CTLA-4, as well as ACT, radiotherapy and chemotherapy, to further unleash the cytotoxic capacity of T cells, which, as will be discussed, can become highly sensitized to adenosine-mediated immunosuppression.