ArticleFrontiers in oncology2026
Metabolic syndrome as an independent predictor of response and survival in locally advanced gastric cancer treated with neoadjuvant immunochemotherapy.
Article in Frontiers in oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Metabolic syndrome (MetS) is prevalent in gastric cancer patients. The obesity paradox, where metabolic excess is associated with improved outcomes in patients receiving immune checkpoint inhibitor (ICI) therapy, remains uninvestigated in locally advanced gastric cancer (LAGC) treated with neoadjuvant immunochemotherapy. We evaluated MetS as a dual predictor of pathological response, immune-related adverse events (irAEs), disease-free survival (DFS), and overall survival (OS). Methods: This multicenter retrospective study included 680 LAGC patients treated with neoadjuvant PD-1 inhibitor plus chemotherapy followed by D2 gastrectomy. MetS was defined using NCEP-ATP III criteria, with East Asian-specific waist-circumference cut-points (≥90 cm men, ≥80 cm women) evaluated as a prespecified sensitivity analysis. Logistic regression, restricted cubic spline (RCS), Kaplan-Meier analysis, multivariable Cox regression for DFS and OS, and decision curve analysis were performed, and a MetS-inclusive nomogram was developed for pathological complete response (pCR) prediction. Results: MetS was present in 157/680 patients (23.1%). After multivariable adjustment for age, sex, BMI, cT stage, cN stage, PD-L1 CPS, MSI status, TyG group, and SII-PNI score, MetS was independently associated with higher pCR (adjusted OR , 1.92, 95% CI 1.06-3.48, P , 0.031) and major pathological response (MPR; OR , 1.58, 95% CI 1.02-2.44, P , 0.040). These associations were materially unchanged after additional adjustment for chemotherapy regimen, PD-1 agent, treatment cycle number, and study center. A positive dose-response trend was observed across MetS component strata (P-trend for pCR, 0.005; for MPR , 0.001). Kaplan-Meier analysis showed superior DFS (log-rank P , 0.017) and OS (log-rank P , 0.019) in MetS patients. Multivariable Cox regression confirmed MetS as an independent favorable DFS predictor (HR , 0.72, 95% CI 0.54-0.96, P , 0.025) and a parallel multivariable Cox model for OS confirmed an independent favorable OS effect (adjusted HR , 0.73, 95% CI 0.55-0.97, P , 0.032). The MetS-inclusive nomogram achieved a bootstrap-corrected AUC of 0.76 for pCR prediction versus 0.64 for the clinical staging model (P , 0.006); bootstrap calibration showed acceptable agreement (Hosmer-Lemeshow P , 0.35), and decision curve analysis demonstrated greater net benefit than the clinical baseline across threshold probabilities of 5-25%. Conclusions: MetS independently predicts improved pathological response and survival without increasing immunotherapy toxicity in LAGC, extending the obesity paradox to the MetS phenotype and supporting an immunometabolic priming effect on ICI efficacy.
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