My life-long work was motivated by Nature 1968 paper by Drs. Karl and Ingegerd Hellstrom, who pointed to the puzzling- and deadly- peaceful co-existence of tumors and anti-tumor killer cells in the same cancer patient. In order to find a biochemical explanation of the “Hellstrom paradox” we first focused on intracellular cAMP in immune cells and established that high levels of cAMP function as the “high fidelity” inhibitors , “OFF” signals in T cells. This was followed by the intuitive focus on and discovery of cAMP-elevating high affinity A2A adenosine receptor (A2AR) as the non-redundant and critical negative physiological regulator of anti-pathogen and anti-tumor immune cells (Nature, 2001; PNAS, 2006). After uncovering in parallel genetic in vivo studies the major T-cell inhibiting role of HIF-1alpha (PNAS, 2002) we proposed the concept of Hypoxia-HIF-1-HRE- and A2AR-cAMP-CRE- governed immunosuppressive transcription (Trends Immunol, 2009). It was then obvious that to enable tumor rejection we must i) target the upstream and downstream stages of this immunosuppressive pathway, ii) provide the preclinical proof of principle and iii) advocate the previously unanticipated immunotherapeutic use of several classes of already available and safe drugs with novel medical motivation. As a “bonus”, these “co-adjuvants” also prevent recruitment of all other known immunosuppressors, including CTLA-4, Tregs, MDSC and TGF-beta among others. The immunotherapeutic R&D of synthetic blockers of A2AR and synthetic tumor oxygenation agents by major Pharma and start-ups, as well as the immediately feasible immunotherapies in combination with breathing good-old oxygen (40%- 60%) (PLOS Biol. 2006; J.Mol.Med 2014; Science Transl. Med. 2015 ) will be discussed. Also to be discussed: the design of current clinical trials and recent data and dramatic examples of tumor rejection rejections by A2AR blocker in some otherwise refractory to chemo- and immunotherapies cancer patients.