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.