Metabolic predictors of response to immunotherapy in locally advanced or metastatic esophageal cancer: unveiling the obesity paradox

INTRODUCTION: PD-1 inhibitor-based immunotherapy is increasingly used for locally advanced or metastatic esophageal cancer, yet the impact of metabolic factors-including the emerging "obesity paradox", wherein high-body mass index (BMI) patients demonstrate a lower risk of all-cause cancer mortality and superior immunotherapy efficacy compared to those with a low-to-normal BMI-on treatment efficacy remains largely unknown. Patients were stratified by BMI and metabolic syndrome (MetS) to assess survival and treatment response; a prognostic nomogram was subsequently developed via LASSO and multivariable Cox regression and validated internally and externally using the respective institutional cohorts. A total of 286 eligible patients with locally advanced or metastatic 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. Elevated BMI serves as an independent predictor of improved outcomes following immunotherapy in locally advanced or metastatic esophageal cancer, whereas the prognostic trend of MetS appears largely dependent on body mass. Furthermore, our validated nomogram integrates these nutritional and metabolic profiles to enable refined prognostic assessment.