IL-11–IL6ST–STAT3 signaling defines a convergent inflammatory axis in esophageal cancer subtypes

Esophageal cancer (EC) is an aggressive malignancy characterized by poor survival outcomes and strong links to chronic inflammatory signaling. Interleukin-11 (IL-11) has emerged as a cytokine of interest in tumorigenesis and therapy resistance. This study investigated the expression, prognostic implications and functional relevance of IL-11 signaling in EC. IL-11 pathway components were analyzed in 50 surgically resected EC and adjacent normal tissues using RT-qPCR and immunohistochemistry (IHC). Histological subtype-stratified analyses were performed for esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Functional assays in KYSE-410 cells evaluated the effect of IL-11 neutralization on viability, migration, and pathway activation. RNA-sequencing, reverse-phase protein array (RPPA), clinical, and survival data from the TCGA-ESCA cohort were analyzed to validate pathway activation and prognostic associations. Additionally, murine RNA-sequencing datasets following anti-IL-11 or anti-IL-11 receptor treatment were examined to assess downstream transcriptional effects. IL-11, COX-2, and STAT3 mRNA levels were significantly upregulated in tumors compared with matched normal epithelium (p < 0.05) accompanied by increased nuclear phosphorylation of STAT3 (Tyr705). TCGA analyses confirmed elevated expression of IL-11 pathway components in EC. Elevated IL11 expression showed a trend toward reduced overall survival and was significantly associated with poorer disease-free survival. While IL11, STAT3, and PTGS2 expression did not differ significantly between EAC and ESCC, receptor-level signaling components IL6ST (gp130) and JAK1 were significantly higher in EAC, with RPPA data demonstrating increased pSTAT3 (Tyr705) and e-cadherin levels in this subtype. Downstream transcriptional analyses revealed subtype-specific STAT3 programs, with proliferation and invasion genes enriched in ESCC and survival-associated mediators elevated in EAC. Neutralization of IL11 significantly reduced cell viability (IC50 = 1 µg/mL), impaired migration, and suppressed pSTAT3 activation. These findings identify the IL-11/IL6ST/JAK1/STAT3/COX-2 axis as a central inflammatory signaling pathway in esophageal cancer. Although ligand expression is comparable across subtypes, receptor-level signaling in EAC suggests pathway sensitization rather than ligand abundance as a key determinant of signaling intensity. Functional inhibition of IL-11 attenuates tumor-promoting phenotypes, supporting IL-11 signaling as a biologically relevant and potentially pan-histologic therapeutic target in esophageal cancer.