AbstractBackgroundAn ever‐increasing number of efforts are focused on identifying effective biomarkers for immune checkpoint inhibitors (ICIs). Cytokines and chemokines are critical to tumor growth, metastasis, tumor angiogenesis, and the immune response against tumor cells. In the study here, we determined the correlation between circulating cytokines/chemokines and the clinical benefit of ICIs for non‐small cell lung cancer (NSCLC) patients.MethodsPeripheral blood samples were collected before and during treatment (at 12th week). Plasma levels of cytokines/chemokines and specific stress response markers were measured using the Bio‐Plex Pro Human Cytokines Grp I Panel (27‐plex), an APEX1 detection kit, and a human LAP(TGF‐β1) immunoassay kit. A Mann–WhitneyU‐test or Wilcoxon signed‐rank test and a Cox proportional hazards model were employed for statistical analysis.ResultsIn the ICI monotherapy cohort, a high level of IL‐6 at pretreatment or an elevation of IL‐6, IL‐8, FGF2, CXCL10, CCR1, PDFGB, TNF, and APEX1 posttreatment was associated with poor progress‐free survival (PFS). A posttreatment elevation (defined herein as change rate) of CXCL10 was also associated with poor overall survival (OS). In the combinational therapy group, a high level of IL‐12, IL‐17A, FGF2, VEGF, and APEX1 at pretreatment and an elevation of CCL2 posttreatment were associated with poor PFS. A high level of IL‐9, FGF2, PDFGB, CCL4, TFGB, and APEX1 at pretreatment and an elevation of IL‐13, CSF2, and CCL2 at posttreatment were associated with poor OS of patients receiving combination therapy.ConclusionsThe study here suggests that circulating cytokines/chemokines are feasible, noninvasive biomarkers for predicting clinical benefit of ICI treatment for NSCLC. Distinct circulating factor profiles were observed in individuals receiving ICI monotherapy or combination therapy.