Cytokine-driven cancer immune evasion mechanisms

Cytokines play a dynamic crucial role in orchestrating homeostasis, immune responses, and the hallmarks and enabling characteristics of cancer cells, particularly by promoting tumor-inflammation and facilitating cancer immune evasion. By dysregulating cytokine production or hijacking signaling pathways, intrinsically or extrinsically, cancer cells can create an immunosuppressive tumor microenvironment that enables them to escape anti-tumor immune responses and promote survival, tumor growth, angiogenesis, metastasis and resistance to anticancer therapies, particularly immunotherapies. Despite extensive research, significant gaps remain in our understanding of cytokines, due to their pleiotropic and context-dependent nature, which varies based on cell type, tissue environment, and cytokine balance. While cytokines are typically classified as pro-inflammatory or immunosuppressive, most of them can act in both ways. Targeting cytokine signaling pathways holds substantial clinical potential, serving as prognostic and predictive biomarkers of response, and therapeutic targets that could improve anti-tumor outcomes, as demonstrated in various preclinical and clinical studies, either as monotherapy or in combination with anticancer therapies, including immunotherapies. For this reason, research focused on their understanding, particularly in how cytokines reshape the tumor microenvironment and the development of therapeutic strategies that target cytokine signaling has garnered increasing attention from the scientific community in recent years. In this review, we will describe the central role of cytokines in cancer, focusing on cytokine-driven mechanisms that contribute to the suppression of anti-tumor immune responses. We will uncover how cancer cells can exploit cytokine signaling pathways to dampen the immune response, promote tumor growth, facilitate metastasis, and enable resistance to anticancer therapies. Key cytokines, such as TGF-β, IL-10, LIF, VEGF, IFNγ, IL-2, IL-12, IL-1, IL-6, IL-8 and TNF-α will be described for their central role in cancer and immune evasion. Furthermore, we will discuss strategies aimed at targeting these cytokines signaling pathways as promising approaches that can improve anti-tumor immune responses and clinical outcomes, particularly in combination with cancer immunotherapies.