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Alleviating hypoxia to improve cancer immunotherapy

Oncogene volume 42, pages 3591–3604 (2023)Cite this article

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Abstract

Tumor hypoxia resulting from abnormal and dysfunctional tumor vascular network poses a substantial obstacle to immunotherapy. In fact, hypoxia creates an immunosuppressive tumor microenvironment (TME) through promoting angiogenesis, metabolic reprogramming, extracellular matrix remodeling, epithelial-mesenchymal transition (EMT), p53 inactivation, and immune evasion. Vascular normalization, a strategy aimed at restoring the structure and function of tumor blood vessels, has been shown to improve oxygen delivery and reverse hypoxia-induced signaling pathways, thus alleviates hypoxia and potentiates cancer immunotherapy. In this review, we discuss the mechanisms of tumor tissue hypoxia and its impacts on immune cells and cancer immunotherapy, as well as the approaches to induce tumor vascular normalization. We also summarize the evidence supporting the use of vascular normalization in combination with cancer immunotherapy, and highlight the challenges and future directions of this overlooked important field. By targeting the fundamental problem of tumor hypoxia, vascular normalization proposes a promising strategy to enhance the efficacy of cancer immunotherapy and improve clinical outcomes for cancer patients.

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Fig. 1: The multifaceted effects of hypoxia in the tumor landscape.
Fig. 2: HIF modulates cancer cell-ECM interactions and remodeling.
Fig. 3: Hypoxia contributes to tumor immune escape.
Fig. 4: Normalization of tumor vasculature alleviates tumor hypoxia: structural and functional alterations in tumor blood vessels.
Fig. 5: Tumor vascular normalization strategy synergizes with immune checkpoint blockade (ICB) therapy to promote tumor regression.

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Acknowledgements

The authors thank Richard Knight for helpful and constructive criticisms.

Funding

This work has been supported by the MUR-PNRR M4C2I1.3 PE6 project PE00000019 Heal Italia (CUP: E83C22004670001) to GM, EC, MA, MF, MP; and by Associazione Italiana per la Ricerca contro il Cancro (AIRC) to GM (IG 2022 ID 27366; 2023-2027), and to EC (IG#22206; 2019-2023). Work has been also partially supported by Regione Lazio through LazioInnova Progetto Gruppo di Ricerca n 85-2017-14986; n 33 & 55-2021-T0002E0001.

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Authors and Affiliations

  1. Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy

    Peng Fan, Eleonora Candi, Massimiliano Agostini, Mauro Piacentini, Bernassola Francesca, Bove Pierluigi, Mauriello Alessandro, Novelli Giuseppe, Rovella Valentina, Scimeca Manuel, Sica Giuseppe, Tisone Giuseppe, Ying Wang & Gerry Melino

  2. National Clinical Research Center for Hematologic Diseases, Cyrus Tang Medical Institute, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Prevention, Soochow University, 215123, Suzhou, China

    Peng Fan, Naidong Zhang & Yuhui Huang

  3. Institute of Biotechnology, Academy of Military Medical Science, Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, 100071, Beijing, China

    Qiang Sun

  4. The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, 215123, Suzhou, China

    Yufang Shi

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  1. Peng Fan
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TOR Centre

  • Bernassola Francesca
  • , Bove Pierluigi
  • , Mauriello Alessandro
  • , Novelli Giuseppe
  • , Rovella Valentina
  • , Scimeca Manuel
  • , Sica Giuseppe
  • , Qiang Sun
  • , Tisone Giuseppe
  •  & Ying Wang

Contributions

PF, YH, YS, and GM conceived the project; PF prepared the first draft; PF, GM, YH, and YS wrote the manuscript; PF, NZ prepared figures. All of the Authors have approved this submitted version.

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Correspondence to Yufang Shi, Yuhui Huang or Gerry Melino.

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GM and YS are members of the Editorial Board of Oncogene. All of the other authors declare no other conflict of interest.

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Fan, P., Zhang, N., Candi, E. et al. Alleviating hypoxia to improve cancer immunotherapy. Oncogene 42, 3591–3604 (2023). https://doi.org/10.1038/s41388-023-02869-2

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