Another approach for limiting the intratumoral interstitial adenosine is the oxygenation of the TME (293). As mentioned, hypoxia promotes build-up of extracellular adenosine at least by inducing upregulation of CD39 and CD73 as well as downregulation of adenosine transporters. Indeed, in pre-clinical models, respiratory hyperoxia (60% oxygen) lowers intra-tumoral adenosine levels (9), tumor growth rates (9), metastasis formation (293) and increases survival of tumor-bearing mice (9, 293). Mechanistically, this treatment boosts MHC-I levels on the tumor-cell surface (9), the presence of CD8+, CD69+, or CD44+ cells within the TME (293) and reduces the presence of Tregs (293) as well as the latter's capacity to express CD39, CD73, CTLA-4, or FoxP3 (293). Moreover, increased oxygenation of tumors not only averts angiogenesis through reduction of VEGF concentration (9), but also dampens expression of molecules associated with immune dysfunction, such as TGF-β, CD39, CD73, A2AR, A2BR and COX-2 (9, 293), the rate-limiting enzyme of PGE2 biosynthesis, while increasing the mRNA levels of pro-inflammatory agents, such as IL-2, and IL-12a (293).