During the past 40 years, cytokines and cytokine receptors have been extensively investigated as either cancer targets or cancer treatments. A strong preclinical rationale supports therapeutic strategies to enhance the growth inhibitory and immunostimulatory effects of interferons and interleukins, including IL-2, IL-7, IL-12 and IL-15, or to inhibit the inflammatory and tumour-promoting actions of cytokines such as TNF, IL-1β and IL-6. This rationale is underscored by the discovery of altered and dysregulated cytokine expression in all human cancers. These findings prompted clinical trials of several cytokines or cytokine antagonists, revealing relevant biological activity but limited therapeutic efficacy. However, most trials involved patients with advanced-stage disease, which might not be the optimal setting for cytokine-based therapy. The advent of more effective immunotherapies and an increased understanding of the tumour microenvironment have presented new approaches to harnessing cytokine networks in the treatment of cancer, which include using cytokine-based therapies to enhance the activity or alleviate the immune-related toxicities of other treatments as well as to target early stage cancers. Many challenges remain, especially concerning delivery methods, context dependencies, and the pleiotropic, redundant and often conflicting actions of many cytokines. Herein, we discuss the lessons learnt from the initial trials of single-agent cytokine-based therapies and subsequent efforts to better exploit such agents for the treatment of solid tumours.
Cytokines are key mediators of cell communication in the tumour microenvironment.
Some cytokines contribute to host antitumour responses, but the production and function of many cytokines is dysregulated in cancer.
A robust rationale supports the use of both cytokines and cytokine antagonists in cancer therapy.
Despite strong preclinical evidence, neither cytokines nor cytokine antagonists have been effective as monotherapies in patients with advanced-stage cancers.
New approaches in this area include exploiting cytokines to enhance the actions or reduce the adverse effects of other cancer treatments, treatment at earlier disease stages and using the cytokine profile of each tumour type to define how best to leverage cytokines.
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The work of F.R.B. is supported by Cancer Research UK programme grant A25714.
F.R.B. is on the scientific advisory board of Verseau Therapeutics and is an adviser to iOmix Therapeutics. D.J.P. declares no competing interests.
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Propper, D.J., Balkwill, F.R. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol 19, 237–253 (2022). https://doi.org/10.1038/s41571-021-00588-9
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