STAT wars: how STATopathies sabotage innate immunity

PURPOSE OF REVIEW: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is a central conduit linking cytokine signals to immune and tissue homeostasis. Over the past decade, a rapidly expanding spectrum of STATopathies, monogenic inborn errors of immunity caused by loss or gain-of-function mutations in individual STAT genes, has been recognized. This review integrates emerging evidence highlighting that, while STAT proteins have been extensively characterized in adaptive immunity, innate immune mechanisms remain insufficiently explored in many STATopathies, even though they are central to host defense, inflammation, and immune regulation. RECENT FINDINGS: Recent studies have delineated cell-specific roles of individual STATs in innate lineages, including monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells. Novel insights reveal how aberrant STAT signaling disrupts interferon responsiveness, pathogen sensing, cytokine feedback, and myeloid cell differentiation. Parallel therapeutic advances, such as JAK inhibitors or cytokine blockade and early gene-correcting are reshaping management of STATopathies. SUMMARY: Recognition of innate immune dysregulation as an important driver of STATopathies broadens diagnostic and therapeutic horizons. Integrating innate immune profiling into clinical evaluation may refine prognostication and treatment selection, while mechanistic understanding of STAT control in myeloid lineages paves the way for precision immunomodulation and future curative interventions.