Adenosine, deriving from ATP released by dying cancer cells and then degradated in the tumor environment by CD39/CD73 enzyme axis, is linked to the generation of an immunosuppressed niche favoring the onset of neoplasia. The effects of adenosine are mediated by four adenosine receptors, named A1, A2A, A2B and A3, that are widely expressed on several immune cell populations. A critical role of this nucleoside is emerging in the modulation of myeloid cell subsets accumulation and functions into tumor microenvironment, providing new insights that might be useful for the development of novel therapeutic approaches aimed to undermine the immune privileged sites where cancer cells grow and proliferate