Metabolic Predictors of Response to Immunotherapy in Unresectable Locally Advanced Esophageal Cancer: Unveiling the Obesity Paradox

Introduction: PD-1 inhibitor-based immunotherapy is increasingly used for unresectable locally advanced esophageal cancer, yet the impact of metabolic factors—and the emerging "obesity paradox"—on treatment efficacy remains largely unknown. Methods Patients were stratified by body mass index (BMI) and metabolic syndrome (MetS) to assess survival (OS/PFS) and treatment response (CR/PR/SD/PD); a prognostic nomogram was subsequently developed via LASSO and multivariable Cox regression and validated internally and externally using the respective institutional cohorts. Results A total of 305 eligible patients with unresectable locally advanced esophageal cancer from two medical centers were included. Patients with high BMI or MetS demonstrated significantly superior overall survival, progression-free survival, and objective response rates to anti-PD-1 therapy. These groups exhibited favorable immune profiles, characterized by a lower pan-immune inflammation value (PIV) and a higher combined positive score (CPS). A prognostic nomogram was successfully constructed and validated, incorporating four independent predictors: gender, BMI, TNM stage, and PIV. The model demonstrated high predictive accuracy for 24- and 36-month overall survival in both internal and external validation cohorts, with well-fitted calibration curves. Conclusion Elevated BMI and MetS correlate with improved outcomes following immunotherapy in unresectable locally advanced esophageal cancer patients. Furthermore, our validated nomogram enables refined prognostic assessment through metabolic risk stratification.