Cytokines from malignant T cells in CTCL downregulate filaggrin and suppress skin barrier function. In healthy skin, filaggrin promotes integrity of the skin barrier. In cutaneous T-cell lymphoma, malignant T cells produce the cytokines IL-13, IL-22, and OSM, which bind to cytokine receptors on surrounding keratinocytes. This activates the JAK-STAT pathway and downregulates filaggrin expression. Filaggrin deficiency in the epidermis causes defects in the skin barrier, which, in turn, promotes inflammation, microbial dysbiosis, and infections, and may even fuel malignant T-cell growth. JAK inhibitors, such as tofacitinib, reverse these effects and can help restore skin barrier function in CTCL.