Novel trends in cancer treatment research are focused on targeting the tumor microenvironment, thereby developing chemo-immunotherapeutic strategies which not only directly kill tumor cells, but also trigger the anti-tumor immune effector responses. Ectonucleotidases (CD39 and CD73)-generated extracellular adenosine and cyclooxygenase-2 (COX2)-derived prostaglandin E2 (PGE2) are amongst the tumor microenvironmental factors that have emerged as attractive targets in this regard. Both comprise a pivotal axis in tumor progression and immune escape via autocrine and paracrine activation of a common intracellular signaling pathway, the cAMP–protein kinase A (PKA) pathway, in cancer and immune cells. In this review, we venture a potential and realistic strategy that this adenosine–PGE2/cAMP nexus is targetable at different levels, thereby pointing out a ‘two hit’ chemo-immunotherapeutic proposition: direct killing of tumor cells on one hand, and the rescuing of endogenous anti-tumor immune response on the other. The reviewed experimental, preclinical and clinical data provide the proof of concept that ‘two hit’ multilevel pharmacological manipulation of adenosine–PGE2/cAMP nexus is achievable within the tumor microenvironment.