Therapeutic targeting of the hypoxic tumour microenvironment

Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia. Hypoxia is a common feature of tumours, contributes to many of the hallmarks of cancer and influences responses to anticancer therapies. Thus, strategies to eliminate and/or exploit tumour hypoxia have long been explored, although with limited success to date. Herein, the authors describe new insights into hypoxia biology, discuss the implications of these advances for novel hypoxia-directed therapeutic strategies, and review the progress made with longstanding methods for targeting hypoxic tumours. Key points O 2 deficiency (euhypoxia), and mutations that have similar effects on patterns of gene expression (pseudohypoxia), have widespread effects on tumour evolution and sensitivity to anticancer agents. Hypoxia-activated prodrugs have been widely investigated for targeting hypoxic tumour cells, but their clinical development has been compromised by a failure to assess hypoxia (and other relevant biomarkers) in individual tumours. Electron-affinic radiosensitizers mimic some of the effects of O 2 in radiation biology and might have applications in highly hypofractionated radiotherapy protocols that are increasingly used to control oligometastatic disease. Hypoxia and associated features of the tumour microenvironment (adenosine, acidosis and nutrient deficiencies) are profoundly immunosuppressive; agents that alleviate hypoxia and/or acidosis can enhance the efficacy of immune-checkpoint inhibitor