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Cited by 3,110Cytokine Signaling Pathways and InteractionsTGF-β signaling in diseasesPsoriasis: Treatment and Pathogenesis

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

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Johnson, Daniel E., O'Keefe, Rachel A., Grandis, Jennifer R.·2018·Nature Reviews Clinical Oncology
DOI 10.1038/nrclinonc.2018.8PMC PMC5858971
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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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  • IL-6 is a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6-STAT3 pathway.

    “IL-6 is also a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6–signal transducer and activator of transcription 3 (STAT3) pathway (18–26, 61–65).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [26]

    The IL-6 section describes IL-6 as a major mediator of inflammation and important in cancer, and discusses arthritis as an inflammatory condition involving IL-6. The STAT3 section says JAK/STAT3 mediates many IL-6 effects in tumours, but it does not establish that IL-6 acts mainly through STAT3 across inflammation, autoimmunity and cancer; the JAKs section also identifies other signalling pathways. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • IL-6/JAK/STAT3 signaling is implicated in many solid tumors, promoting tumor growth and progression while hindering antitumor immunity.

    “The IL-6/JAK/STAT3 signaling pathway has also been implicated in many solid tumors, where it has been shown to promote tumor growth and progression while hindering antitumor immunity.”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Johnson et al., 2018

  • Other inhibitors against the IL-6-STAT3 signaling pathway are under development.

    “Other inhibitors against the IL-6–STAT3 signaling pathway are under development (19, 21, 24–26, 76, 374).”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [26]

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Cited by

Sorted by citations

Authors
Johnson, D. E., O'Keefe, R. A., & Grandis, J. R.
Affiliations
University of California, San Francisco (US)
Corresponding author
Grandis, Jennifer R.
ORCID
Venue
Nature Reviews Clinical Oncology
Publisher
Springer Science and Business Media LLC
Published
2018-02-06
Volume
15
Issue
4
Pages
234-248
ISSN
  • 1759-4774 (ISSN-L)
  • 1759-4782
DOI
10.1038/nrclinonc.2018.8
PMC
PMC5858971
OpenAlex
W2786987313
Cited by
3,110
References
12
Citations by year
2026: 370 · 2025: 454 · 2024: 476 · 2023: 443 · 2022: 450 · 2021: 399 · 2020: 294 · 2019: 168 · 2018: 53
FWCI
24.01
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Reviews Clinical Oncology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Cancer Institute (R35CA231998, R01CA077308, P50CA097190)
  • National Institute of Dental and Craniofacial Research (F31DE026951, R01DE023685, R01DE024728)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
interleukin-6, JAK inhibitors, STAT3 inhibitor, tumor microenvironment, antitumor immunity, cancer immunotherapy, immune checkpoint inhibitors, combination therapy, hematologic malignancies, solid tumors, IL-6 receptor
MeSH terms
Receptors, Chimeric Antigen, Interleukin-6 Inhibitors, Antineoplastic Agents, Humans, Neoplasms, Signal Transduction, Interleukin-6, Cell Proliferation, STAT3 Transcription Factor, Janus Kinases, Molecular Targeted Therapy, Tumor Microenvironment

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