Interferon signaling pathways in health and disease

Interferons (IFNs) are a family of cytokines that orchestrate a wide range of antiviral, immunoregulatory, and antitumor activities. This review provides a comprehensive overview of the molecular mechanisms underlying IFN signaling, including both canonical JAK (janus kinases)-STAT (signal transducers and activators of transcription) pathways and non-canonical branches such as MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)-AKT (protein kinase B)-mTOR (mechanistic target of rapamycin). The intricate interplay between these signaling modules and transcriptional, epigenetic, and post-transcriptional regulators is essential for maintaining immune homeostasis and tailoring context-dependent immune responses. Under physiological conditions, IFNs are essential for host defense, driving antiviral gene expression, activating innate immune cells, and shaping adaptive immune responses, including T and B cells. Conversely, dysregulation of IFN signaling contributes to the development of autoimmune diseases, neuroinflammation, cardiovascular disorders, and cancer. Tumor cells can exploit IFN-induced suppressive molecules to evade immune attack. The currently emerging therapeutic strategies of IFN signaling have evolved into a dual strategy: replacement therapy in immunodeficient states, and pathway inhibition in autoimmune conditions. Additionally, IFN-based combination therapies with immune checkpoint blockade and radiotherapy have demonstrated synergistic potential but require precise control of dosing and timing to avoid immune exhaustion. Advances in single-cell transcriptomics, proteomics, and metabolomics are providing novel insights into IFN heterogeneity, enabling the development of personalized IFN-based treatments. This review highlights the clinical implications and emerging strategies to harness or restrain IFN signaling for therapeutic benefit.