Proteomic and metabolomic profiling reveals dysregulation of immune states, mucin-type glycosylation and steroid metabolism in extramammary Paget's disease.

Extramammary Paget's disease is a rare cutaneous adenocarcinoma characterized by mucin-rich Paget cells and chronic inflammation, yet its molecular basis remains unclear. To systematically characterize the proteomic and metabolomic landscape of EMPD, uncover immune heterogeneity, and identify molecular pathways underlying tumor progression and microenvironment remodeling. We performed integrated proteomic and metabolomic analyses on 92 male tumor patients and 30 healthy controls, identifying 10,217 proteins and 1466 metabolites. Extramammary Paget's disease lesions exhibited broad activation of inflammatory pathways. Immune profiling further uncovered substantial inflammatory heterogeneity, delineating immune-cold and immune-hot subtypes, with the latter associated with stronger invasive potential. Aberrant mucin-type glycosylation was also prominent, featuring Tn-modified MUC1 and MUC5AC accompanied by elevated GALNT7, GALNT6, GALNT4, and ST6GAL1, which correlated with inflammatory intensity. Metabolomic data demonstrated elevated levels of testosterone, dehydroepiandrosterone, and related intermediates in tumor tissues, indicating an androgen-enriched metabolic profile in extramammary Paget's disease. These findings reveal immune, glycoproteomic, and metabolomic pathways in extramammary Paget's disease pathogenesis and provide novel insights for molecular classification and therapeutic targeting.