Baseline IL-6 independently predicts severe immune-related toxicity and poor survival in advanced gastric cancer...

Immune checkpoint inhibitors (ICIs) improve survival in advanced gastric cancer (GC), yet predicting therapeutic benefit versus toxicity remains challenging. Elevated interleukin-6 (IL-6) is linked to poor prognosis, but whether it simultaneously influences immune-related adverse events (irAEs) and how this relationship impacts survival remains unclear.

We retrospectively analyzed 244 patients with advanced GC treated with ICIs. Predictors of high-grade irAEs were evaluated using Firth's penalized logistic regression to mitigate small-sample bias. Independent prognostic factors for overall survival (OS) were identified via multivariable Cox analysis and validated using propensity score matching (PSM). Causal mediation analysis was performed to assess whether the effect of IL-6 on OS was mediated through irAEs. Biological mechanisms were explored using TCGA-STAD transcriptomic data.

Baseline IL-6 was a strong independent predictor of high-grade irAEs (OR = 2.74, P < 0.001) and inferior OS (P = 0.019), a finding confirmed after PSM. Mediation analysis did not demonstrate a statistically significant mediating effect of irAEs on the relationship between IL-6 and survival. Bioinformatic validation linked high IL-6 expression to hyper-inflammatory signaling (TNF/IL-17 pathways) and immunosuppressive M2 macrophage infiltration.

Baseline IL-6 was independently associated with both severe immune-related toxicity and inferior overall survival, suggesting that elevated systemic IL-6 reflects an adverse inflammatory state in which toxicity does not necessarily correspond to improved therapeutic outcomes. These findings support further evaluation of IL-6 in risk stratification and warrant prospective investigation into its potential therapeutic modulation in combination with ICIs.