Abstract
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.
Data availability
The datasets generated and/or analysed during the current study are available in the Zenodo repository: [https://doi.org/10.5281/zenodo.19217128](https:/doi.org/10.5281/zenodo.19217128)TCGA-ESCA RNA-sequencing and RPPA datasets analysed in this study are publicly available from the Genomic Data Commons (GDC) data portal ([https://portal.gdc.cancer.gov/](https:/portal.gdc.cancer.gov)) and cBioPortal for Cancer Genomics ([https://www.cbioportal.org/](https:/www.cbioportal.org)). Murine RNA-sequencing datasets were obtained from the Gene Expression Omnibus (GEO) under accession number GSE128940, from which processed data were derived. All processed datasets used in the study are publicly available in the Zenodo repository.
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Acknowledgements
We thank all the EC patients for their permission and cooperation to participate in the study. We highly appreciate ICMR, GoI for their support in funding this research.
Funding
The study was funded by Indian Council of Medical Research (ICMR), GoI under research grant No. 5/3/8/72/2020-ITR.
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S.A.R: Data interpretation, Experimentation, Drafting the manuscript, Statistical analysis, Result interpretation for revision, A.A.P,: Design of the study, conceived the work and drafting the manuscript, performed the experiments, supervision, acquisition of funds and evaluation of results F.A.G: Provided samples. QA: Experimentation, U.M., Experimentation, D.A: Logistic support, supervision and reviewed the manuscript Z.R.: Histopathology N.A.D., A.M.B., Cell line experimentation S.M., Assisted to conduct experiments.
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All procedures done involving human participants were done in compliance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The ethical sanction was attained from Institutional Ethical Committee. The study protocol was approved by the Ethics Committee of SK Institute of Medical Sciences (IEC/SKIMS protocol # RP 16/2020).
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Rasool, S.U.A., Pandith, A.A., Ganie, F.A. et al. IL-11–IL6ST–STAT3 signaling defines a convergent inflammatory axis in esophageal cancer subtypes. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46619-2
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DOI: https://doi.org/10.1038/s41598-026-46619-2
