Skin AllergoOncology: A Framework for Decoding the Context-Dependent Functions of the IgE-FcεRI Axis in Cutaneous...

The immunoglobulin E (IgE)-FcεRI axis, a central mediator of allergic inflammation, plays a dual role in cutaneous tumor immunity. Epidemiological evidence presents a paradox: atopic dermatitis (AD) promotes keratinocyte carcinogenesis, yet systemic allergic responses are associated with reduced melanoma risk. This review proposes the "Skin AllergoOncology" framework to resolve this paradox. The framework defines the skin as the only human organ in which two antagonistic IgE-FcεRI programs, protective immune surveillance and chronic pro-tumor inflammation, can be spatially juxtaposed. It is organized around three analytical dimensions: IgE repertoire quality, inflammatory kinetics, and effector-cell polarization state. We critically examine the epidemiological AD-keratinocyte carcinoma association, highlighting the confounding role of immunosuppressive therapies, and review the molecular infrastructure enabling dual functional outputs, including antigen focusing by trimeric FcεRI on Langerhans cells and microenvironment-dependent mast cell polarization. We contend that the absence of direct functional evidence for protective IgE in humans represents the central question for the next decade, and we propose a five-year dual-engine roadmap to identify the human protective IgE signature. This framework informs risk-stratified surveillance, engineered IgE antibody therapy, and the long-term oncological safety assessment of anti-allergic biologics.