Hypoxia: Turning vessels into vassals of cancer immunotolerance

Abstract

Hypoxia is a universal feature of solid cancers caused by a mismatch between cellular oxygen supply and consumption. To meet the increased demand for oxygen, hypoxic cancer cells (CCs) induce a multifaceted process known as angiogenesis, wherein new vessels are formed by the sprouting of pre-existing ones. In addition to providing oxygen for growth and an exit route for dissemination, angiogenic vessels and factors are co-opted by CCs to enable the generation of an immunotolerant, hypoxic tumor microenvironment, leading to therapeutic failure and mortality. In this review, we discuss how hypoxia-inducible factors (HIFs), the mechanistic target of rapamycin (mTOR), and the unfolded protein response (UPR) control angiogenic factors serving both vascular and immunomodulatory functions in the tumor microenvironment. Possible therapeutic strategies, wherein targeting oxygen sensing might enhance anti-angiogenic and immunologically-mediated anti-cancer responses, are suggested.

Keywords: Angiogenesis; Cancer; HIF; Hypoxia; Hypoxia-inducible factors; Immunotherapy; Oxygen sensing; Targeted therapy; Tumor microenvironment; UPR; mTOR.