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  • Review Article
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Therapeutic targeting of the hypoxic tumour microenvironment

Nature Reviews Clinical Oncology volume 18, pages 751–772 (2021)Cite this article

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Abstract

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.

Key points

  • O2 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 O2 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 inhibitors.

  • New evidence demonstrates that suppression of O2 consumption using inhibitors of the mitochondrial electron transport chain can relieve tumour hypoxia in patients.

  • Anticancer therapies that induce vascular damage can exacerbate tumour hypoxia, triggering a vascular repair process that supports tumour regrowth while also suppressing homology-directed repair of DNA damage. Both of these responses to treatment-induced hypoxia can be targeted therapeutically.

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Fig. 1: Hypoxia and associated TME stresses have key roles in cancer biology.
Fig. 2: Radioresistance of hypoxic tumours and mechanisms of radiosensitization by O2 and EARs.
Fig. 3: Targeting hypoxic tumours with HAPs.
Fig. 4: Influence of tumour hypoxia on immune cell recruitment and function.
Fig. 5: Novel therapeutic strategies associated with responses to hypoxia induced by vascular-damaging agents.

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Acknowledgements

Aspects of this Review were informed by valuable discussions with J.M. Brown (Stanford University, Stanford, CA, USA), C.P. Hart (University of California, San Francisco, CA, USA), M.P. Hay (University of Auckland, New Zealand), M. Vissers (University of Otago, Christchurch, New Zealand) and F.W. Hunter (Janssen Research and Development, Philadelphia, PA, USA).

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  1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Dean C. Singleton & William R. Wilson

  2. Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand

    Dean C. Singleton & William R. Wilson

  3. Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

    Dean C. Singleton

  4. Auckland City Hospital, Auckland, New Zealand

    Andrew Macann

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Singleton, D.C., Macann, A. & Wilson, W.R. Therapeutic targeting of the hypoxic tumour microenvironment. Nat Rev Clin Oncol 18, 751–772 (2021). https://doi.org/10.1038/s41571-021-00539-4

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