The promising results of the first in-human clinical study using A2AR antagonists for treatment of renal cell carcinoma highlight two decades of research into the hypoxia-A2-adenosinergic pathway. Importantly, clinical responses have been observed in patients who previously progressed on anti-PD-1/PDL-1 therapy, emphasizing the clinical importance of targeting A2AR signaling in cancer immunotherapies. Recently, it has been shown that systemic oxygenation weakens all known stages of the hypoxia-A2-adenosinergic axis. Therefore, we advocate the clinical use of systemic oxygenation and oxygenation agents in combination with A2AR blockade to further improve cancer immunotherapies. This approach is expected to completely eliminate the upstream (hypoxia-HIF-1α) and downstream (adenosine-A2AR) stages of the immunosuppressive hypoxia-adenosinergic signaling axis. This might be a necessary strategy to maximize the therapeutic benefits of A2AR antagonists and increase susceptibility of tumors to cancer treatments.Copyright © 2020 Elsevier Ltd. All rights reserved.