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Understanding microenvironment\u2010primed immune responses is essential to elucidate the phenotypic\/functional changes MCs undergo, and thus understand their contribution to diseases and predict the most effective therapeutic strategies. We exposed primary human MCs to cytokines mimicking a T1\/pro\u2010inflammatory (IFN\u03b3), T2\/allergic (IL\u20104\u2009+\u2009IL\u201013), alarmin\u2010rich (IL\u201033) and pro\u2010fibrotic\/pro\u2010tolerogenic (TGF\u03b2) microenvironment. We investigated MC surface receptor expression, activation, cytokine, histamine, and prostaglandin D2 release, and performed transcriptomics to define shared and unique genetic features. Using machine learning, we extracted minimal cytokine\u2010activated signatures and performed gene set variation analysis (GSVA), single\u2010cell clustering, and pseudotime analyses on tissue MCs from skin and respiratory diseases. MCs exposed in\u00a0vitro to IFN\u03b3 acquire an antigen\u2010presenting phenotype (HLA\u2010DR+), increase IgE\u2010mediated responses and histamine release, while TGF\u03b2 inhibits activation and boosts integrin \u03b1v\u03b23 expression. IL\u201033 primarily drives cytokine (GM\u2010CSF, IL\u20105, IL\u201010, IL\u201013) and chemokine production (IL\u20108, MCP\u20101, MIP\u20101\u03b1) and facilitates mixed IgG\u2010IgE responses. Among uniquely expressed genes, 245 were highly informative to discriminate cytokine\u2010primed MCs. GSVA revealed MC IL\u20104\u2009+\u2009IL\u201013 signatures enriched in atopic dermatitis and psoriasis, IFN\u03b3 in COVID\u201019 infection and cystic fibrosis, IL\u201033 in COVID\u201019 and chronic obstructive pulmonary disease (COPD) and TGF\u03b2 in pulmonary fibrosis (PF) and chronic rhinosinusitis. Furthermore, we detected positive IL\u201033\/TGF\u03b2 priming in eosinophil\u2010high COPD. Minimal cytokine\u2010activated signatures identified disease\u2010cytokine\u2010specific MC clusters and pseudotime trajectories, suggesting involvement of MCs in fibrosis (COPD\/PF), T1\/alarmin\u2010driven inflammation (COVID\u201019) and mixed T1\/T2 inflammatory responses (AD\/psoriasis). In conclusion, in cytokine\u2010driven settings, MCs are phenotypically and functionally diverse. Thus, unique MC signatures will help to identify cytokine\u2010primed MCs and predict the efficacy of anti\u2010cytokine treatment in MC\u2010driven diseases.<\/jats:p>","DOI":"10.1111\/all.70052","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T07:22:18Z","timestamp":1757488938000},"page":"3077-3094","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Microenvironment\u2010Driven Mast Cell Plasticity: Insights From Cytokine\u2010Activated Gene Signatures in Skin and Respiratory Diseases"],"prefix":"10.1111","volume":"80","author":[{"given":"Chiara","family":"Tontini","sequence":"first","affiliation":[{"name":"Department of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation The University of Manchester  Manchester 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