Elevated PTK6 expression is associated with tumor immune microenvironment remodeling and predicts poor prognosis in endometrial carcinoma

Background Uterine corpus endometrial carcinoma (UCEC) incidence rises globally, with >50% of advanced/recurrent patients showing poor response to immune checkpoint inhibitors due to inadequate biomarkers. Protein tyrosine kinase 6 (PTK6), aberrantly expressed in malignancies and linked to tumor progression, lacks defined clinical significance in UCEC. Methods Multi-omics analysis utilized UCEC RNA-seq (TCGA/GEO) and proteomics (CPTAC). PTK6 protein interactors from STRING were used for functional enrichment analysis. Tumor microenvironment (TME) was assessed via ESTIMATE (stromal/immune scores), TIMER3 (immune infiltration), and TCIA (immunophenoscore, IPS). Immunohistochemistry (IHC) validation ( n = 200) explored the prognostic value. Results PTK6 was upregulated in UCEC ( p < 0.001) with promoter hypomethylation (median β: 0.32 vs. normal 0.52, p < 0.001), highest in microsatellite instability-high (MSI-H) subtype, and correlated with tumor mutational burden (TMB). High PTK6 expression associated with worse overall survival (OS) in both entire cohort (HR = 2.065, 95% CI 1.060–4.203, p = 0.033) and MSI-H subtype (HR = 8.562, 95% CI 2.226–32.930, p = 0.0018). Exploratory analysis suggested low PTK6-linked reduced progression-free survival in POLE subtype (HR = 10.48, 95% CI 1.063–103.4, p = 0.044; wide CI suggests caution). PTK6-related genes were mainly involved in ERBB signaling, PD-1/PD-L1 immune checkpoint in cancers, and focal adhesion. Upregulated PTK6 was associated with an altered TME (increased neutrophils, decreased CD8 + T cells, reduced IPS; all p < 0.05). IHC confirmed PTK6 overexpression as an independent poor prognostic factor for OS (HR = 5.050, 95% CI 2.136–11.943, p < 0.001), associating with aggressive clinicopathological features (all p < 0.05). Conclusion PTK6 represents a context-dependent prognostic biomarker linked to tumor immune microenvironment remodeling in UCEC, suggesting its potential utility for immunotherapeutic optimization.