Prognostic and metastasis-associated roles of IL-6 and IL-8 in patients with stage IV gastric cancer

Background: Cytokine-driven inflammation is increasingly recognized as a key determinant of tumor progression and metastatic behavior in gastric cancer. Interleukin-6 (IL-6) and interleukin-8 (IL-8) are central mediators of immune suppression, angiogenesis, and systemic inflammatory activation, yet their clinical significance in advanced gastric cancer remains insufficiently defined. Methods: Pre-treatment blood samples from 186 patients with HER2-negative stage IV gastric cancer treated at Severance Hospital between May 2019 and March 2025 were analyzed. Serum IL-6 and IL-8 levels were quantified by ELISA in patients with stage IV gastric cancer prior to systemic therapy. Patients were stratified into high- and low-expression groups using predefined cutoffs. PD-L1 expression was assessed by immunohistochemistry using the PD-L1 IHC 22C3 pharmDx assay and quantified by combined positive score (CPS). Associations with metastatic patterns and overall survival (OS) were assessed using nonparametric tests and Kaplan-Meier analysis. Results: High cytokine expression was strongly associated with inferior clinical outcomes. Patients with high IL-6 levels (≥4.6862 pg/mL) showed significantly reduced OS compared with the IL-6-low group (HR 1.96, 95% CI 1.31-2.94; P=0.0008). A similar but more pronounced effect was observed for IL-8, where high expression (≥7.5801 pg/mL) was associated with markedly worse survival (HR 2.79, 95% CI 1.89-4.10; P < 0.0001). No correlation was observed between IL-6 and PD-L1 expression or between IL-8 and PD-L1 expression at any CPS cutoff. Cytokine levels also demonstrated metastatic pattern specificity: IL-6 was significantly elevated in patients with bone metastasis (P = 0.018) including IL-8 (P = 0.039), whereas IL-8 was markedly increased in those with liver metastasis (P = 0.002). These findings suggest that systemic cytokine elevation reflects both tumor aggressiveness and distinct metastatic phenotypes. Conclusion: IL-6 and IL-8 are strong, accessible biomarkers associated with poor survival and characteristic metastatic patterns in advanced gastric cancer. Their integration into clinical risk assessment may improve biological stratification and inform future therapeutic strategies.