Th2-primed innate immune amplification defines a distinct atopic dermatitis endotype

Atopic dermatitis (AD) is clinically heterogeneous, but reproducible molecular endotypes remain incompletely defined. By integrating >1,300 lesional and non-lesional skin transcriptomes from 30 studies, we identified two robust AD endotypes that share a conserved lesional core program of barrier disruption and type 2 activation. In contrast to endotype 1 (62%), endotype 2 (38%) was distinguished by a compact 108-gene innate-inflammatory signature (including IL1B and IL6), increased myeloid infiltration, and Staphylococcus aureus-associated dysbiosis. Endotype assignment was stable across longitudinal datasets, with only limited, non-systematic switching upon systemic treatment. Analysis of trial and observational data provided preliminary evidence for lower clinical response and higher residual molecular activity under dupilumab in endotype 2 compared to endotype 1. Interaction modeling of Th2 and innate module activity revealed a Th2-amplified innate state that predicts endotype 2, paralleling functional experiments in which IL-1b/IL-6 synergize with Th2 cytokines to exacerbate keratinocyte inflammation and to impair keratinocyte differentiation. Our findings offer new insights into the biological diversity of AD and establish a robust foundation for mechanistic stratification, with implications for therapeutic strategies.