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  • Review Article
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Targeting the IL-6/JAK/STAT3 signalling axis in cancer

Nature Reviews Clinical Oncology volume 15, pages 234–248 (2018)Cite this article

Subjects

Key Points

  • The IL-6/JAK/STAT3 signalling pathway is aberrantly hyperactivated in patients with chronic inflammatory conditions and in those with haematopoietic malignancies or solid tumours

  • Multiple cell types in the tumour microenvironment produce IL-6, leading to activation of JAK/STAT3 signalling in both tumour cells and tumour-infiltrating immune cells, which can promote tumour-cell proliferation, survival, invasiveness, and metastasis

  • STAT3 is hyperactivated in tumour-infiltrating immune cells and acts to negatively regulate neutrophils, natural killer cells, effector T cells, and dendritic cells while positively regulating populations of myeloid-derived suppressor cells and regulatory T cells

  • Targeting components of the IL-6/JAK/STAT3 signalling pathway can inhibit tumour cell growth and relieve immunosuppression in the tumour microenvironment

  • Inhibitors of IL-6, the IL-6 receptor, or JAKs have all received FDA approval for various malignancies, and other novel inhibitors of the IL-6/JAK/STAT3 signalling pathway are currently in clinical and/or preclinical development

  • Investigations of the efficacy of IL-6/JAK/STAT3 inhibitors, in combination with immune-checkpoint inhibitors, are warranted

Abstract

The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.

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Figure 1: IL-6 signalling pathways.
Figure 2: Signalling downstream of the IL-6 receptor.
Figure 3: Inhibitors of the IL-6/JAK/STAT3 signalling pathway.

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Acknowledgements

The work of the authors is supported by grants from the US NIH (R01 DE24728 and P50 CA097190 to D.E.J., F31 DE026951 to R.A.O., R01 DE023685 and P50 CA097190 to J.R.G.) and the American Cancer Society (CRP-13-308-06-COUN to J.R.G.).

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  1. Department of Otolaryngology – Head and Neck Surgery, University of California, San Francisco, CA, USA

    Daniel E. Johnson, Rachel A. O'Keefe & Jennifer R. Grandis

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  1. Daniel E. Johnson
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  2. Rachel A. O'Keefe
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  3. Jennifer R. Grandis
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All authors made a substantial contribution to all aspects of the preparation of this manuscript.

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Correspondence to Jennifer R. Grandis.

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Johnson, D., O'Keefe, R. & Grandis, J. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15, 234–248 (2018). https://doi.org/10.1038/nrclinonc.2018.8

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