Since the discovery of the first two cytokines, Interleukin (IL)−1α and IL-1β in 1974 by Charles A. Dinarello, (Dinarello, Goldin, & Wolff, 1974), numerous cytokines have been discovered, representing a complex network of small proteins essential for regulating and coordinating almost all biological contexts, including body’s homeostasis, immune responses, and intercellular communication during development, tissue damage and remodeling, response to infections, and disease, such as cancer. Cytokines are primarily produced by immune cells but are also secreted by tumors, acting as crucial mediators in various signaling pathways that influence tumor behavior both intrinsically and extrinsically. Tumor cells can manipulate these proteins and their signaling to foster their progression. The biological effects of cytokines are diverse; they can either suppress or activate immune responses, thereby contributing to the formation of an immunosuppressive tumor microenvironment (TME) and, depending on the context, can either suppress tumor growth or enable cancer cells with mechanisms for survival and proliferation.

Cytokines are context-dependent molecules with pleiotropic and dual roles depending on the tissue and cell type involved. While cytokines are typically classified as pro-inflammatory or immunosuppressive, most of them can act in both ways. The balance among multiple cytokines, rather than the influence of a single cytokine, often dictates specific phenotypes. Dysregulation of cytokines can result in disease. Increased levels of pro-inflammatory cytokines are commonly associated with autoimmune diseases, while both pro-inflammatory and anti-inflammatory cytokines play important roles in cancer, depending on the tumor stage.

Cancer cells exhibit a set of functional capabilities crucial for tumor formation, referred to as the hallmarks of cancer. Initially described were six features: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing/accessing vasculature, and activating invasion and metastasis (Hanahan & Weinberg, 2000). This framework has been expanded to include new hallmarks such as avoiding immune destruction and reprogramming metabolism, along with enabling characteristics like tumor-promoting inflammation or genomic instability (Hanahan & Weinberg, 2011). Recent updates have introduced additional characteristics, including unlocking phenotypic plasticity, nonmutational epigenetic reprograming, polymorphic microbiomes and senescent cells (Hanahan, 2022). Importantly, cytokines and their signaling pathways are key determinants in orchestrating these hallmarks, influencing processes from the most known modulation of the immune system and tumor-promoting inflammation, to apoptosis, proliferation, angiogenesis, cellular metabolism, phenotypic plasticity, epigenetic reprogramming, senescence and metastasis (Fig. 1). Among these functions, cytokine signaling pathways are crucial for establishing an immunosuppressive TME that inhibit anti-tumor effector immune cell functions, which are pivotal for cancer immune evasion. The immune system plays a pivotal role in every step of the cancer immune cycle, from tumor initiation to metastatic colonization, by identifying cancer cells as foreign entities and target them (Chen & Mellman, 2013). In addition, the immune system and tumor cells engage in a dynamic and complex interactions that determine the elimination, control, or escape of cancer cells, known as the immunoediting process, and cytokines play a central role in orchestrating tumor progression within these processes.

Despite advances over five decades of research, significant gaps remain in our understanding of cytokines. In addition, the number of identified cytokines continues to grow, with interleukin (IL)−40 being the most recently identified in 2017 (Catalan-Dibene et al., 2017), and IL-30 to IL-40 over the past 20 years. Research on these recently discovered cytokines is limited, highlighting the need for further investigation to elucidate their roles in diseases, particularly in cancer and immune evasion, as well as their therapeutic potential. Future research on both newly identified and well-characterized cytokines will provide new insights in the upcoming years for developing innovative therapeutic approaches, particularly for cancer immunotherapies.

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.