Role of anti-tumorigenic cytokines in gastrointestinal cancers

Gastrointestinal (GI) cancers are among the deadliest worldwide, with millions of cases and deaths annually. In the U.S., they account for over 25 % of cancer-related deaths, with colorectal cancer (CRC) leading in incidence and mortality, followed by pancreatic, liver, gastric, and esophageal cancers. These malignancies vary in cellular origin and etiology but share common risk factors, which contribute to chronic inflammation and immune dysfunction, influencing cytokine-driven pathways that shape the tumor environment. This review outlines and discusses the anti-tumorigenic properties of key/select cytokines such as interleukin (IL)-12, IL-15, IL-2, and interferon (IFN)-γ with recent discoveries, therapeutic advancements, and persistent challenges in cytokine biology for GI cancers. We searched with keywords for articles published in the last 20 years. IL-12, IL-15, IL-2, and IFN-γ all regulate or promote natural killer (NK)-cells and T-lymphocytes to suppress GI tumor growth. When deleted in tumor models, there is an increase in other inflammatory mediators that result in cancer progression. The literature supports an inverse relationship between low cytokine levels and advanced-stage disease. While the literature suggests these cytokines are not as beneficial or potentially harmful as single agents, when used in GI cancer treatment as an adjuvant in combination therapies or with innovative delivery methods, there is statistically significant therapeutic efficacy with improved clinical outcomes, median survival, and tumor suppression. The applicability of anti-tumorigenic cytokines (IL-12, IL-15, IL-2, and IFN-γ) as biomarkers of diagnosis and indicators of prognosis is being recognized with emphasis on their capabilities as therapeutic targets and adjuvant therapies in GI cancers.