Low Serum Interleukin-6 Levels Enhance the Efficacy of Neoadjuvant Immunotherapy in Locally Advanced Esophageal Squamous Cell Carcinoma.

Abstract

Background: Neoadjuvant immunotherapy has become a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC), but predictive biomarkers for treatment efficacy remain limited. This study investigates the role of serum interleukin-6 (IL-6) levels as a prognostic biomarker in patients receiving neoadjuvant immunotherapy for ESCC. Methods: A retrospective cohort study was conducted in 47 patients with locally advanced ESCC who underwent neoadjuvant immunochemotherapy followed by esophagectomy. Pretreatment serum levels of IL-6 and the combined positive score were analyzed. Pathological responses were evaluated using the College of American Pathologists Tumor Regression Grade system, and survival outcomes were assessed by Kaplan-Meier analysis. IL-6 knockout mice models were used to validate the impact of IL-6 on anti-PD-1 therapy efficacy. Results: Lower pretreatment serum IL-6 levels were significantly associated with better pathological response compared with higher IL-6 levels. Elevated IL-6 levels (>61.495 pg/mL) were identified as an independent risk factor for poorer disease-free survival and overall survival. IL-6 deficiency enhanced the efficacy of anti-PD-1 therapy in mice, reducing tumor burden compared with wild-type controls. Conversely, exogenous IL-6 administration attenuated anti-PD-1 effects. Mechanistically, lower serum IL-6 levels increased CD8⁺ T cell activation and decreased the regulatory T cell proportion during immunotherapy. Conclusions: Low serum IL-6 levels enhance the efficacy of neoadjuvant immunotherapy in locally advanced ESCC.