Figure 1: CD73-generated adenosine orchestrates the tumor-stroma interplay to promote cancer growth. The concerted action of CD39 and CD73 represents the main pathway for extracellular adenosine production in the tumor microenvironment. These two ectonucleotidases are expressed not only by tumor stromal cells (such as endothelial cells or tumor-associated regulatory T cells) but also by certain cancer cells, allowing for the conversion of extracellular ATP (released by dying tumor cells) into adenosine. Adenosine exerts its tumor-promoting effects in paracrine and autocrine fashion by activating adenosine receptors expressed by tumors cells, endothelial cells, or immune cells. Activation of A2A adenosine receptors inhibits IFN- production and cytotoxic killing by CD8+ T cells and promotes CD4+ cells differentiation into T-regulatory cells. This immunosupressive effect is strengthened by adenosine action on the tumor-surrounding endothelium which consists in repressing T-cell homing to tumors through the downmodulation of adhesion proteins such as ICAM-1, VCAM-1 or P-selectin. Simultaneously, A2A and A2B engagement on endothelial cells also enhance the production of proangiogenic factors including VEGF, b-FGF, and IL-8. This effect is mediated by HIF-1 and synergizes with the hypoxic tumoral microenvironment. Finally, CD73-generated adenosine also promotes tumor development by directly acting on cancer cells through A2A and/or A2B adenosine receptor activation and subsequent enhancement of invasiveness and chemotactic response.