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Background There is a heterogenous clinical response following chemoradiotherapy (CRT) in esophageal squamous cell carcinoma (ESCC). Therefore, we aimed to study signaling pathway genes that affect CRT sensitivity and prognosis. Methods Gene expression analyses were performed in the GEO and TCGA datasets. A immunohistochemistry (IHC) analysis was performed in pretreatment biopsies. Results MMP13 was found to be highly expressed in the “Pathologic Complete Response (pCR)” and “Complete Remission (CR)” and “Alive” groups. Th17 cells and MMP9/13 showed a negative correlation in immune infiltration analysis. In GSEA analysis, IL-4 and IL-13 signaling pathways were highly enriched in patients exhibiting high MMP expression in pCR and CR groups. IHC results suggested higher MMP13 & IL-4 and lower IL-17A & RORC expression in the CR group compared to the <CR (CR not achieved) group. Survival analyses further indicated that the prognosis was worse in the high IL-17A group (p = 0.046, HR = 2.15). Next, a prognostic model was established. In the training cohort, AUCs for the 1/2/3/4/5-year OS were all greater than 0.70. In the two validation cohorts, 1-year AUCs were also >0.70, and the model could well distinguish high-risk and low-risk subgroups. Conclusion The above results may provide guidance for developing novel treatment and prognostic strategies in ESCC patients.