Interleukin 27 (IL-27) in gastrointestinal cancers: from dual roles in tumor immunity to immunotherapeutic opportunities.

Gastrointestinal (GI) cancers continue to account for a major global cancer burden, with immune dysregulation recognized as a key determinant of their initiation and progression. Interleukin-27 (IL-27), a heterodimeric cytokine of the IL-12 family, has emerged as a pivotal but paradoxical regulator of tumor immunity in the GI cancers. IL-27 signals through the WSX-1/gp130 receptor complex, activating signal transducer and activator of transcription (STAT1) - and STAT3-dependent transcriptional pathways, yielding opposing outcomes. STAT1-dominant signaling promotes cytotoxic T-cell proliferation, T helper 1 (Th1) polarization, and natural killer (NK) cell cytotoxicity. However, STAT3-mediated responses induce IL-10, enhances regulatory T (Treg) cells suppression, stimulates myeloid-derived suppressor cells (MDSCs) activity, and upregulates programmed death ligand 1 (PD-L1), thereby facilitating immune evasion. These contrasting effects manifest in tumor-specific patterns: IL-27 demonstrates potent anti-tumor activity in experimental colorectal (CRC) and pancreatic cancer models, while elevated IL-27 associates with disease progression in hepatocellular carcinoma (HCC). Recent translational advances include IL-27-expressing viral vectors, dendritic cell platforms, and IL-27-blocking antibodies, underscoring its therapeutic duality. Overall, IL-27 functions as a context-dependent cytokine whose final effect on tumor progression is determined by the intrinsic characteristics of each tumor, the composition of tumor microenvironment (TME) and the interaction between immune and epithelial cells. Understanding the mechanisms that drive the dual roles of IL-27 across different GI cancers will be important for designing rational immunotherapeutic strategies that either enhance or inhibit IL-27 activity.