O2-sensing and HIF regulation: from oxygen homeostasis to tumor-associated immune responses.

Oxygen is needed to generate adenosine triphosphate (ATP) via aerobic respiration in mitochondria. Hypoxia-when the tissue's oxygen demand exceeds its supply-characterizes not only sites of acute inflammation but also many tumors and their microenvironment. But even then, (immune) cells must ensure sufficient ATP synthesis. Under hypoxic conditions, hypoxia-inducible factors (HIFs) are capable of adapting cellular metabolism by induction of hundreds of target genes that, among others, regulate glycolysis, cell survival, and angiogenesis. This may hold true for immune cells under homeostatic conditions when they are forced to fight against pathogens and for tumor cells when the activation of HIFs enables tumor cells to survive in oxygen-deficient tissues. In addition, HIF activation in many tumors promotes the creation of an immunosuppressive tumor microenvironment that prevents immune cells from effectively fighting the tumor. Therefore, promising approaches have been made in the combination of immune therapies with HIF inhibition. In this review, we highlight that a better understanding of the role of hypoxic adaptation requires considering the HIF stabilization patterns of tumor type, tumor stage, and the immune cells within the tumor microenvironment to optimize therapeutic efficacy.