IFNE (interferon epsilon) is a constitutively expressed type I interferon uniquely localized to reproductive tract epithelia, where it maintains basal expression of interferon-stimulated genes and provides immunosurveillance against infections 1. Unlike canonical type I interferons (α/β), IFNE is not pathogen-induced but rather hormonally regulated during the estrous cycle and pregnancy 23. IFNE signals through IFNAR1/2 and JAK-STAT pathways with lower potency than IFNα/β in vitro, yet demonstrates robust in vivo efficacy 1. Mechanistically, IFNE protects the female reproductive tract from sexually transmitted viruses including Zika virus through constitutive expression that resists viral antagonism 4. IFNE also functions as an intrinsic tumor suppressor in high-grade serous ovarian cancer by directly inhibiting tumor cells and activating anti-tumor immunity while preventing myeloid-derived suppressor cell accumulation 5. Beyond the female tract, IFNE is expressed in testicular spermatogenic cells and macrophages, protecting against viral infection and inflammation 6. Recently, IFNE loss in Barrett's esophagus reduced immune infiltration, implicating broader roles in mucosal immune surveillance 7. IFNE is highly upregulated in alveolar macrophages responding to Mycobacterium tuberculosis 8. These findings establish IFNE as a specialized immunoregulator maintaining tissue-specific antiviral and anti-tumor defenses.