Interleukin-27 signaling axis (IL-27 axis) (IL-27 axis)

Interleukin-27 (IL-27) is a heterodimeric cytokine of the IL-12 family, composed of the p28 (IL-27p28) and Epstein-Barr virus-induced gene 3 (EBI3) subunits (UniProt P40225, Q8NEV9). It signals through a receptor complex consisting of IL-27RA (WSX-1) and gp130, which activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, primarily STAT1 and STAT3 (PubMed: 15345516). The IL-27 signaling axis serves as a critical immunomodulator with dual roles: it can promote early Th1 differentiation while also acting as a potent inhibitor of inflammation by suppressing Th17 cells and inducing IL-10-producing regulatory T cells (PubMed: 28234311). In oncology, IL-27 is frequently exploited by tumors to create an immunosuppressive environment; it induces the expression of multiple immune checkpoints, including PD-L1, LAG-3, and TIGIT, on tumor-infiltrating lymphocytes (PubMed: 33009416). Consequently, therapeutic targeting of this axis with monoclonal antibodies like SRF388 (Tizatug) is designed to block these suppressive signals and restore anti-tumor immunity (PubMed: 34155111). Beyond cancer, the axis is a target of interest in chronic inflammatory and autoimmune diseases due to its role in maintaining immune homeostasis (PubMed: 25139105).

Other names

IL-27/IL-27R axisInterleukin-27 receptor complexIL-27/WSX-1/gp130 pathwayIL-27 signaling pathway

Therapeutic agents targeting the Interleukin-27 signaling axis, such as monoclonal antibodies, work by binding to the IL-27 cytokine or its receptor subunit IL-27RA to prevent the formation of the signaling complex. This blockade inhibits the activation of STAT1/STAT3, preventing the downstream induction of immune-checkpoint molecules like PD-L1 and TIM-3, thereby restoring the activity of cytotoxic T lymphocytes and Natural Killer cells within the tumor microenvironment (PubMed: 33009416, PubMed: 34155111).