Atopic dermatitis (AD), commonly referred to as eczema, atopic eczema, or neurodermatitis, is one of the most prevalent inflammatory skin conditions, affecting approximately 15 %-20 % of children and up to 10 % of adults (Laughter et al., 2021). It ranks highest among skin diseases in terms of disability-adjusted life-years (DALYs) (Xue et al., 2022).

The precise pathogenesis of AD remains elusive. The inflammatory process can be categorized into acute and chronic phases. During the acute phase, a Th2-type immune response predominates. Cytokines secreted by Th2 cells, including IL-4, IL-5, and IL-13, stimulate IgE production and promote eosinophil activation and infiltration (Yamamura et al., 2024). These cytokines also inhibit keratinocyte differentiation, thereby further compromising skin barrier function. In the chronic phase, the Th1 immune response becomes progressively more prominent. Cytokines produced by Th1 cells, such as IFN-γ and TNF-α, enhance macrophage and T cell activation, contributing to chronic inflammation and lichenification (Lee et al., 2018). Recent studies have highlighted the significant role of Th17 and Th22 cells in AD pathogenesis. IL-17, secreted by Th17 cells, facilitates neutrophil infiltration and keratinocyte proliferation, perpetuating the inflammatory response and exacerbating skin barrier disruption (Zhang et al., 2023). Importantly, this transition involves more than simple cytokine shifts-mechanical barrier disruption from scratching induces DAMPs (Damage-associated molecular patterns) release and microbiota dysbiosis, creating a self-perpetuating inflammatory loop. Thus, clinical studies revealed AD is frequently associated with dysbiosis of the skin microbiome, particularly the overgrowth of Staphylococcus aureus and its release of antigens, which directly activate T cells and keratinocytes, intensifying inflammation (Nakamura et al., 2013). Consequently, local tissue immune abnormalities, impaired skin barrier function, and microbial dysbiosis are critical components in the pathogenesis of AD.

Currently, the clinical management of AD primarily relies on glucocorticoids (TCS) and oral antihistamines as first-line therapies (Sidbury et al., 2023). In recent years, significant advancements have been made in the research and development of Th2-targeted therapies aimed at addressing pruritus in AD. Promising clinical trials include monoclonal antibodies targeting IL-4, IL-13, and IL-31, as well as phosphodiesterase-4 inhibitors and JAK inhibitors (Guttman-Yassky et al., 2021, Blauvelt et al., 2017, Saeki et al., 2022). However, the complex inflammatory immune endotypes of AD have posed challenges to the development and efficacy of targeted therapies. Identifying the specific immune endotypes and mediators involved in AD could facilitate upstream inhibition of immune activation, thereby providing novel targets and strategies for more effective treatment.

In this study, we established a Th1/Th2/Th17 mixed immune endotypes-AD mouse model through skin injury combined with peanut allergen sensitization. This model was designed based on the clinical observation that AD patients exhibit concurrent Th2 and non-Th2 signatures in their chronic lesions (Schuler et al., 2023, Meledathu et al., 2025). By employing antibiotic treatment and utilizing gene-deficient mice, we demonstrated that in the development of mixed immune endotypes of AD, epidermal Langerhans cells are primarily in charge of the recognition and presentation of allergens. However, dendritic cells (DCs) are crucial antigen-presenting cells that recognize colonizing bacteria in addition to allergens. The STING signaling pathway plays a pivotal role in DCs activation and induces Th1/Th2/Th17 inflammatory responses in AD, and maintains IgG2a and IgG1 production. Our work therefore suggests that targeting STING may serve as a potential therapeutic strategy for controlling mixed immune endotypes-AD.