Dynamic Integrative Immune Profiling Reveals Early Biomarkers of Response and Prognosis in Advanced Gastric Cancer Treated with Nivolumab Plus Chemotherapy

<b>Background</b>: Nivolumab plus chemotherapy is a standard first-line treatment for advanced gastric cancer (GC), but reliable early biomarkers for predicting treatment outcomes remain lacking. This study aimed to identify early immunological predictors through dynamic immune profiling. <b>Methods</b>: Fifty patients with advanced or unresectable GC receiving nivolumab plus XELOX or FOLFOX were enrolled. Peripheral blood was collected at baseline, week 1, and week 6. Plasma biomarkers (Granzyme B, Ki-67, CXCL10, IFN-γ, TGF-β1) were measured by ELISA, and immune cell subsets, including cytotoxic T cells, immune checkpoint-positive populations, and memory T-cell subsets, were analyzed by flow cytometry. Cutoffs were defined by medians, established thresholds for NLR and lymphocyte count, and criteria for long-term response (≥9.5 months). Associations with response and progression-free survival (PFS) were evaluated using Kaplan-Meier analysis, Cox regression, and ROC curves. <b>Results</b>: Early responders exhibited significant increases in Granzyme B and CXCL10, with ΔGranzyme B alone and in combination with ΔKi-67 predicting response with high accuracy. A lower week 1 neutrophil-to-lymphocyte ratio was associated with long-term benefit. Elevated week 1 CD8⁺ T-cell proportion and greater decreases in PD1⁺CD69⁺Ki-67⁺CD8⁺ T cells were linked to improved PFS. Higher baseline PD1⁺LAG-3⁺Ki-67⁺CD8⁺ T-cell levels and combined TIM-3⁺/LAG-3⁺ expression enhanced prognostic stratification. Additionally, elevated baseline activated TEMRA cells and declines at week 6 in the same subset correlated with better outcomes. <b>Conclusions</b>: These findings highlight the clinical utility of serial immune monitoring to enable early treatment stratification and guide personalized immunotherapy strategies in advanced GC.