Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment.

Hypoxia (low O2 ) is a ubiquitous microenvironmental factor promoting cancer progression, metastasis and mortality, owing to the ability of cancer cells to co-opt physiological angiogenic responses. Notwithstanding, the pathophysiological induction of angiogenesis results in an abnormal tumor vasculature, further aggravating hypoxia in a feed-forward loop that limits the efficacy of molecular targeted therapies. Recent studies suggest that besides their canonical roles, angiogenic factors promote a panoply of immunosuppressive effects in the tumor microenvironment. Therefore, intratumoral hypoxia emerges as a hitherto unrecognized mechanism evolutionarily repurposing angiogenic molecules as (patho)physiological immunomodulators. On the other hand, antiangiogenic therapies could be aimed at impeding both tumor growth and immunotolerance towards cancer cells, a beneficial effect that can be countered if hypoxia signaling pathways are left unchecked, leading to therapeutic failure. This review summarizes evidence supporting the hypothesis that hypoxia acts as a common pathophysiological mechanism of resistance to immunotherapeutic and antiangiogenic agents whilst proposing potential strategies to curtail resistance and mortality in patient bearing solid malignancies.