A longitudinal atlas of human psoriatic skin reveals the mechanisms of anti-IL-23 therapy in disrupting the type 17 inflammatory circuit.

Biologic therapies targeting the IL-23/IL-17 axis have transformed the treatment of psoriasis and show lasting efficacy after treatment cessation. To investigate the immune mechanisms behind these biologics, we performed single-cell RNA sequencing and spatial transcriptomics on matched pre- and post-treatment psoriatic skin samples from patients treated with IL-23 blockade and followed longitudinally for 36 weeks after treatment cessation. IL-23 blockade resulted in a durable reduction in IL-17-producing CD8+ tissue-resident memory T cells via a c-MAF-IL-7 axis and suppressed IL-17+ T cell infiltration. IL-23 blockade also reduced APOE+/IL34+ fibroblasts. Pro-inflammatory dendritic cells were concomitantly decreased by limiting fibroblast-derived IL-34, which was a central signal driving monocyte-to-dendritic cell differentiation. Furthermore, IL-23 blockade reduced spatial vascular expression of CCL19 and CCL21, which attenuated immune cell infiltration. Our findings provide a high-resolution map of IL-23 inhibition leading to stable cellular and molecular remodeling that breaks the inflammatory loop in psoriatic skin.