Role of cytokine-based immunotherapy approaches in gastrointestinal cancers

Gastrointestinal (GI) cancers are among the most common leading causes of cancer-related mortality globally and they are the leading cause of cancer-related mortality in the US. Immune checkpoint inhibitor (ICI)-based therapies altered treatment paradigm in several tumor types including GI cancers. Despite encouraging results in select GI cancers, response rate is low, and treatment resistance poses a challenge in clinical practice. Cytokines are soluble mediators that regulate immune responses and can either promote or inhibit tumor growth depending on their impact on the tumor microenvironment (TME). In GI cancers, chronic inflammation driven by cytokines such as IL-6, IL-10, TNF-α, and TGF-β facilitates immune evasion and tumor progression. Cytokines contribute to the histopathogenesis of GI cancers by driving chronic inflammation, promoting epithelial-to-mesenchymal transition, and remodeling the TME to favor immunosuppression and angiogenesis. This cytokine-mediated landscape not only supports tumor initiation and progression but also influences systemic therapy outcomes by fostering resistance to chemotherapy and dampening responsiveness to immunotherapy. Integrating cytokine-targeted strategies with ICIs may enhance antitumor immunity by reversing T-cell exhaustion, improving effector T cell infiltration and function, and reprogramming the tumor milieu toward a pro-inflammatory, immune-permissive state potentially overcoming resistance and improving clinical efficacy. While ICIs have attracted most of the research interest in the past decade, cytokine-based therapy is another frontier to be utilized as either a therapeutic agent or a target to regulate cancer immunogenicity. In this review we aim to present a comprehensive discussion about relevant cytokines in GI cancers and explain mechanism of cytokines in immune regulation, discuss therapeutic potential of different cytokines, interleukins, interferons, tumor growth factors and their clinical application in recent clinical trials either alone or combined with other immunotherapeutic agents in GI cancers. Additionally, we discuss the potential limitations and challenges of cytokine-based immunotherapy in GI cancers.