Director of Drug Hypersensitivity Clinical and Research Center, Department of Dermatology, Chang Gung Memorial Hospital 

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCAR), can be triggered by either conventional drugs or immune checkpoint inhibitors (ICI). Despite their clinical overlap, the underlying immunopathogenesis and optimal treatment strategies remain elusive. Leveraging cutting-edge single-cell and spatial transcriptomic technologies, we investigated lesional skin and peripheral blood from patients with both traditional drug-induced and ICI-induced SJS/TEN.

In ICI-induced SJS/TEN, single-cell RNA sequencing uncovered abundant macrophage-derived CXCL10 in skin blister cells, driving recruitment of CXCR3⁺ cytotoxic T lymphocytes (CTLs). Trajectory and expression analyses suggest that ICI-activated T cells in circulation initiate inflammation, promoting monocyte-to-macrophage differentiation and homing to skin. TNF signaling was identified as the upstream trigger for CXCL10 expression and CTL activation. Notably, patients receiving TNF blockade demonstrated faster recovery and tolerated continued ICI therapy without recurrence, outperforming corticosteroid-based regimens.

In traditional drug-induced SJS/TEN, we performed integrated single-cell and spatial transcriptomic profiling, which revealed JAK/STAT signaling as a central pathway in epidermal necrolysis. Clonally expanded CD8⁺ tissue-resident memory T cells (Trm), enriched in lesional skin, exhibited high levels of cytotoxic mediators (GNLY, GZMB), pro-inflammatory cytokines, immune checkpoint markers (LAG3, HAVCR2, CTLA4), and activation of the JAK1/3-STAT1 axis. Ex vivo blockade and multiplex immunostaining validated this pathway’s role in disease propagation. In a proof-of-concept clinical trial (NCT06474078), targeting JAK1/3 with tofacitinib accelerated re-epithelialization and resulted in zero mortality, supporting its therapeutic potential.

Our findings highlight distinct but converging therapeutic targets and immune circuits in SJS/TEN pathogenesis driven by different triggers. The combined application of single-cell and spatial transcriptomics provides unprecedented insight into the cellular and molecular architecture of epidermal necrolysis and enables rational therapeutic development for both drug- and ICI-induced SCAR.