Hypoxia (ie, critically reduced oxygen levels) is present in most human tumors (1). Systematic studies on the oxygenation status in the clinical setting have shown that the existence of hypoxic/anoxic subvolumes is a pathophysiological trait in solid malignancies with complex spatial and temporal heterogeneities, both within and between tumors of the same type. For many years, tumor hypoxia has been regarded as an obstacle for the control of tumors treated with standard radiotherapy (RT), some chemotherapies, and photodynamic therapy. During the last two decades, evidence is accumulating suggesting that hypoxia has a strong negative impact driving cancer cells toward a more aggressive phenotype, resulting from an increased mutagenicity (< 0.1% O 2, severe hypoxia), and hypoxia-driven regulation of a plethora of genes, promoting changes of the proteome and metabolome, preferentially through HIF-dependent mechanisms (< 1% O 2, modest-to-moderate hypoxia), ultimately leading to a poorer patient prognosis (2–4). In addition, hypoxia can enhance the expression of stem cell markers (5, 6) and can lead to a substantial inhibition of innate and adaptive antitumor immune responses [eg, recently highlighted in Ref.(7)].

Inter alia, this latter aspect is addressed in a recent review by Ohta in this journal (8). Antitumor immune suppression–and thus tumor progression–can in part be directly mediated by hypoxia itself (adenosine-independent immune suppression) and, to a major part, be driven by HIF-dependent adenosine (ADO) production by immune and cancer cells with subsequent accumulation in the extracellular space (ECS), which contributes to a pro-cancer, hostile tumor microenvironment (9–11).