IL‐27: A Double‐Edged Sword in Immune Regulation via JAK‐STAT Orchestration

Interleukin‐27 (IL‐27) is a multifunctional cytokine produced mainly by innate immune cells that regulates immune responses primarily through the Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) signaling pathway. The role of IL‐27 in immune regulation is complex and often paradoxical, with both pro‐inflammatory and immunosuppressive functions described, depending on the specific immune context and cellular milieu. Here, we systematically discuss the dual regulatory roles of IL‐27 in immune regulation, with a particular emphasis on its role in the JAK‐STAT signaling pathway. We highlight the latest advancements in understanding the functional differences and molecular mechanisms of IL‐27 in both adaptive and innate immune cells. We further elaborate on IL‐27‐mediated immune regulation through nonimmune cells. Understanding the multifaceted and context‐dependent properties of IL‐27 is essential for deciphering the precise role of IL‐27 in health and disease and for developing targeted immunotherapies. This review systematically analyzes the “double‐edged sword” mechanism of IL‐27, providing a theoretical and translational basis for targeting the JAK‐STAT pathway.