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We analyzed 92 EAC specimens using mass spectrometry\u2013based proteomics, comprising 47 female and 45 male tumors from treatment\u2010na\u00efve patients. Differential expression, pathway enrichment, immunohistochemical, and survival analyses were used to identify sex\u2010associated proteomic features and prognostic signatures. Proteomic profiling revealed focal yet biologically meaningful sex differences in EAC. After multiple testing correction, three proteins were differentially expressed: the autosomal protein pregnancy zone protein (PZP), enriched in female tumors, and the Y\u2010chromosome\u2013encoded proteins DDX3Y and RPS4Y1, which were overexpressed in male tumors. At nominal significance, proteins upregulated in female tumors showed marked enrichment of immune\u2010related pathways. Proteins correlated with PZP expression formed a network dominated by complement cascade. Clinically, elevated PZP expression was associated with significantly poorer overall survival specifically in male patients, with no significant association detected in the combined or female\u2010only cohort. Proteome\u2010wide survival analyses further demonstrated distinct sex\u2010specific prognostic landscapes. Our study provides the first comprehensive characterization of sex\u2010associated proteomic differences in EAC. Sex shapes immune\u2010related pathways, prognostic proteomic signatures, and survival associations. PZP emerges as a sex\u2010differential, complement\u2010associated protein with adverse prognostic significance in male patients, highlighting sex as a biologically and clinically relevant variable in EAC.<\/jats:p>","DOI":"10.1002\/ijc.70687","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T07:57:01Z","timestamp":1786521421000},"page":"2595-2605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex\u2010Specific Proteomic Profiling Identifies Pregnancy Zone Protein as a Complement\u2010Linked Marker of Adverse Prognosis in Esophageal Adenocarcinoma"],"prefix":"10.1002","volume":"159","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3537-6011","authenticated-orcid":false,"given":"Alexander","family":"Quaas","sequence":"first","affiliation":[{"name":"Institute of Pathology, Faculty of Medicine and University Hospital of Cologne, University of Cologne  Cologne 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