Navigating the Cytokine Seas: Targeting Cytokine Signaling Pathways in Cancer Therapy

Abstract

Cancer remains one of the leading causes of morbidity and mortality worldwide, necessitating continuous efforts to develop effective therapeutic strategies. Over the years, advancements in our understanding of the complex interplay between the immune system and cancer cells have led to the development of immunotherapies that revolutionize cancer treatment. Cytokines, as key regulators of the immune response, are involved in both the initiation and progression of cancer by affecting inflammation and manipulating multiple intracellular signaling pathways that regulate cell growth, proliferation, and migration. Cytokines, as key regulators of inflammation, have emerged as promising candidates for cancer therapy. This review article aims to provide an overview of the significance of cytokines in cancer development and therapy by highlighting the importance of targeting cytokine signaling pathways as a potential therapeutic approach.

Keywords: IL-6; JAK/STAT signaling; NF–κB; TGF-β; cancer therapy; cytokine signaling; epithelial mesenchymal transition; immune modulation; immunotherapy; inflammation; novel therapies; tumor microenvironment.

Figure 1

Cytokine signaling pathways and their pivotal roles in both inflammation and tumor development. Activation of nuclear factor-κB (NF-κB) via many stimuli (i.e., persistent inflammation in response to pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns) leads to the production of proinflammatory cytokines and mediators by fibroblasts, epithelial cells, and myeloid cells (i.e., dendritic cells (DCs), monocytes, and macrophages). Additionally, tumor-initiating cells recruit macrophages, which, upon activator protein 1 (AP-1) signaling, produce transforming growth factor-β (TGF-β) that suppresses the function of cytotoxic T lymphocytes (CTLs). In response to IL-1β, other cytokines are also produced: IL-6, IL-11, and IL-22 from epithelial and myeloid cells. Furthermore, IL-6 activation of STAT3 signaling is observed in multiple cancer types and induces proliferation, survival, stemness, epithelial–mesenchymal transition (EMT), and migration of transformed cells. T helper 17 (TH17) cells differentiate under the influence of IL-1β, IL-6, and a higher concentration of TGF-β. These cells then release IL-17A and IL-17F (IL-17A/F) in response to IL-23 stimulation from DCs. IL-17 normally stimulates NF-κB to facilitate wound-healing signaling but can also aggravate nascent tumor development. Some cytokines, such as IL-6, TGF-β, or IL-11, may act in an autocrine manner to activate consequently signal transducer and activator of transcription 3 (STAT3), NF-κB, rat sarcoma (RAS)–rapidly accelerated fibrosarcoma (RAF)–mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)–AKT–mTOR signaling to upregulate glycolysis and induce metabolic reprogramming. These pathways can lead to increased migration and epithelial–mesenchymal transition (EMT), increased proliferation, decreased apoptosis, increased migration, and the production of cytokines, including metalloproteinases, vascular endothelial growth factor (VEGF), and IL-8, which in turn induces angiogenesis. Parts of the figure were drawn using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). Copyrights: the authors.