This study aimed to investigate the role of immunotrophic inflammatory markers in assessing the prognosis and treatment-related toxicity in patients with esophageal squamous cell carcinoma (ESCC) undergoing first-line radiotherapy and chemotherapy combined with immunotherapy. We retrospectively enrolled 67 patients with ESCC and determined the optimal cutoff values for prognostic nutrition index (PNI), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) using receiver operating characteristic (ROC) curve analysis. Statistical analysis was performed using SPSS 25.0. The one-, two-, and three-year overall survival (OS) rates were 88.1%, 62.3%, and 57.6%, respectively. The overall effective rate was 82.1% (55/67). ROC curve analysis revealed optimal cutoff values for PNI, NLR, and PLR as 48.35, 3.84, and 150.49, respectively. Patients in the high PNI group, low NLR group and PLR group exhibited significantly higher mOS and mPFS time compared to the control group. Notably, the incidence of grade 2 toxicity and side effects in the PNI ≥ 48.35 group was significantly lower than that in the PNI < 48.35 group. Our findings suggest that pretreatment values of PNI, NLR, and PLR can serve as valuable biomarkers for evaluating the prognosis of ESCC patients undergoing first-line radiotherapy and chemotherapy combined with immunotherapy. Further studies with larger cohorts are warranted to validate these results.© 2025. The Author(s).