Comprehensive pan-cancer characterization of PTPN3 reveals its prognostic, immunological, and tumorigenic significance across human malignancies

Protein tyrosine phosphatase non-receptor type 3 (PTPN3) regulates tumor-cell signaling and lymphocyte activation, but its molecular and clinical associations vary among malignancies. We characterized this heterogeneity through a multi-platform pan-cancer analysis. PTPN3 expression, pathological stage, and survival were evaluated using TCGA, GTEx, TIMER2.0, and GEPIA2. CPTAC/UALCAN data were used to examine total protein abundance and site-specific phosphorylation. cBioPortal was used to characterize genomic alterations and alteration-associated survival. TIMER2.0 estimated cancer-associated fibroblast (CAF) abundance, while STRING, GEPIA2, and functional enrichment analyses characterized PTPN3-associated molecular networks. PTPN3 showed heterogeneous transcript and protein expression across cancers. Higher expression was associated with poorer overall survival in ACC, BRCA, and UCS but more favorable overall survival in KIRC and UCEC. Higher expression was also associated with poorer disease-free survival in ACC, LUSC, and UCS but a more favorable outcome in KIRC. UCEC exhibited the highest alteration frequency, and A716T was observed in LUSC, UCEC, and COAD. Nine phosphorylation sites displayed cancer-type- and site-specific differences across six CPTAC cohorts. PTPN3 expression showed positive or negative correlations with estimated CAF abundance depending on cancer type and algorithm. PTPN3 was positively correlated with EGLN1, RORC, CMYA5, ASB16, and PHKA1, while enrichment analysis highlighted PI3K–Akt signaling and cytoskeleton-related functions. PTPN3 exhibits substantial cancer-type-dependent heterogeneity across molecular, prognostic, phosphorylation, and stromal dimensions. These database-derived associations generate testable hypotheses but do not establish PTPN3 as an independent prognostic or therapeutic biomarker.