The hypoxic tumour microenvironment: A safe haven for immunosuppressive cells and a therapeutic barrier to overcome

Dating back to the seminal work of Paul Ehrlich, the idea of harnessing our immune system to eliminate cancerous cells is now over a century old. In the presence of a functional immune system that so efficiently guards the host against developing neoplasms, tumour cells must evolve sophisticated strategies to escape immune destruction in order to give rise to clinically detectable cancers. A new way of treating cancer would thus be to target the immune system itself rather than the tumour, and extensive studies in randomised trials have cemented the possibility of using immunotherapy for treating advanced-stage cancers. Immunotherapy, however, is only tolerated in a minority of patients and in many cases, patients suffer from adverse immune-related reactions when the immune system goes into overdrive. A primary barrier thwarting the development of effective immunotherapy seems to coalesce into the peculiarities of the tumour microenvironment for which hypoxia is a key feature. Here, we review emerging themes on how hypoxia contributes to immune suppression and obstructs anti-tumour effector cell functions. We discuss the challenges and opportunities relating to the potential for dually targeting hypoxia and the immune system to promote durable and favourable responses in cancer patients.