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 3 independent cohorts of 288 samples, we established an integrated risk assessment framework spanning the entire therapeutic continuum: (i) a baseline predictor for initial responders based on metabolite signatures; (ii) an on-treatment predictor in prognosticating long-term responders among initial ones based on treatment-induced metabolic shift patterns; and (iii) a real-time model based on dual alteration of sphingolipid and glycerophospholipid dynamically stratifying progression risk. Meanwhile, 2 dietary metabolites, garlic-derived S-allyl-L-cysteine and cruciferous vegetable-derived indole-3-carbinol, were confirmed to improve outcomes by promoting NK-cell infiltration and reversing CD8+ T-cell exhaustion. In conclusion, we provide the first metabolomic roadmap for precision chemoimmunotherapy in ESCC, unifying baseline prediction, longitudinal surveillance, and dietary modulation into a clinically actionable paradigm. SIGNIFICANCE: We established a large-scale plasma metabolomic database from patients with ESCC undergoing chemoimmunotherapy, defining the first noninvasive, comprehensive, and precise monitoring framework for treatment response prediction and risk assessment. Our findings reveal clinically actionable dietary metabolites that may serve as readily accessible adjuvants to enhance chemoimmunotherapy efficacy.