Arenas Enrique J
Cancer Epigenetics Group, Josep Carreras Leukaemia Research Institute (IJC), Carretera de Can Ruti, Camí de les Escoles s/n, Barcelona, Spain.
Int Rev Cell Mol Biol. 2025;396:1-54. doi: 10.1016/bs.ircmb.2025.01.004. Epub 2025 Feb 22.
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.
细胞因子在协调体内平衡、免疫反应以及癌细胞的特征和促成特性方面发挥着动态关键作用，特别是通过促进肿瘤炎症和促进癌症免疫逃逸。通过内在或外在地失调细胞因子产生或劫持信号通路，癌细胞可以创造一个免疫抑制性肿瘤微环境，使它们能够逃避抗肿瘤免疫反应并促进存活、肿瘤生长、血管生成、转移以及对抗癌疗法，尤其是免疫疗法的耐药性。尽管进行了广泛研究，但由于细胞因子具有多效性且依赖于背景，其性质因细胞类型、组织环境和细胞因子平衡而异，我们对细胞因子的理解仍存在重大差距。虽然细胞因子通常被分类为促炎或免疫抑制，但它们大多数都可以以两种方式发挥作用。靶向细胞因子信号通路具有巨大的临床潜力，可作为反应的预后和预测生物标志物以及治疗靶点，能够改善抗肿瘤结果，正如各种临床前和临床研究所示，无论是作为单一疗法还是与包括免疫疗法在内的抗癌疗法联合使用。因此，近年来，专注于理解细胞因子，特别是细胞因子如何重塑肿瘤微环境以及开发靶向细胞因子信号的治疗策略的研究越来越受到科学界的关注。在本综述中，我们将描述细胞因子在癌症中的核心作用，重点关注导致抗肿瘤免疫反应抑制的细胞因子驱动机制。我们将揭示癌细胞如何利用细胞因子信号通路来抑制免疫反应、促进肿瘤生长、促进转移并实现对抗癌疗法的耐药性。将描述关键细胞因子，如转化生长因子-β、白细胞介素-10、白血病抑制因子、血管内皮生长因子、干扰素-γ、白细胞介素-2、白细胞介素-12、白细胞介素-1、白细胞介素-6、白细胞介素-8和肿瘤坏死因子-α在癌症和免疫逃逸中的核心作用。此外，我们将讨论旨在靶向这些细胞因子信号通路的策略，这些策略是有前景的方法，可以改善抗肿瘤免疫反应和临床结果，特别是与癌症免疫疗法联合使用时。
