Longitudinal Plasma Metabolomics Guides Dynamic Risk Assessment and Dietary Modulation for Esophageal Squamous Cell Cancer Chemoimmunotherapy

Esophageal squamous cell carcinoma (ESCC) exhibits heterogeneous responses to chemoimmunotherapy, with only a minority achieving durable benefit, necessitating dynamic precision monitoring. Through longitudinal plasma metabolomics of 541 serial samples from 252 ESCORT-1st trial patients receiving chemoimmunotherapy plus three independent cohorts of 288 samples, we established an integrated risk assessment framework spanning the entire therapeutic continuum: (1) a baseline predictor for initial responders based on metabolite signatures; (2) an on-treatment predictor in prognosticating long-term responders among initial ones based on treatment-induced metabolic shift patterns; (3) a real-time model based on dual alteration of sphingolipid and glycerophospholipid dynamically stratifying progression risk. Meanwhile, two dietary metabolites, garlic-derived S-allyl-L-cysteine and cruciferous vegetable-derived indole-3-carbinol, were confirmed to improve outcomes by promoting NK cells infiltration and reversing CD8+ T cells exhaustion. In conclusion, we provide the first metabolomic roadmap for precision chemoimmunotherapy in ESCC, unifying baseline prediction, longitudinal surveillance, and dietary modulation into clinically actionable paradigm.