IMT has led to unprecedented clinical success for some advanced cancer patients and has been accepted as a new pillar of cancer therapy (1). Thus, the identification of biomarkers predicting response to IMT, as well as the development of combinatorial strategies for increasing its effectiveness in more patients, and against a broader range of tumor-types, have become important areas of research (2). The nucleoside adenosine, involved in the regulation of multiple diverse physiological processes either as an intracellular metabolite of nucleic acid synthesis and energy-charge regulation or as an intercellular messenger in neurological, cardiovascular and immunological systems, has recently emerged as a major immuno-metabolomic checkpoint in tumors (3). Conditions of stress, such as hypoxia, lead to the accumulation of extracellular adenosine, predominantly derived from enzymatic ATP catabolism, which can act directly on tumor cells expressing adenosine receptors to promote their growth, survival and dissemination. In addition, adenosine, which under physiological conditions serves as an immuno-regulatory molecule to protect normal tissues from uncontrolled inflammation, can impair anti-tumor immunity, both through the attenuation of protective immune cells including T cells, NK cells, and dendritic cells (DCs), and by enhancing the suppressive capacity of T regulatory cells (Tregs), and myeloid-derived suppressor cells (MDSCs), amongst others. Here we review the targeting of the adenosine pathway to promote immune function and tumor control, with focus on T-cell activity, important experimental findings and an overview of clinical testing.