BackgroundThe circulating predictive factors for the outcomes of advanced non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICIs) remain elusive. We aimed to assess the predictive value of circulating cytokines for outcomes.MethodsSerum samples of 102 advanced-stage NSCLC patients who underwent immunotherapy were collected at baseline. The relative levels of 37 cytokines were detected. PD-L1 expression was also analyzed.ResultsHigher serum CXCL12 levels (top 33%) were a poor predictive biomarker for durable clinical benefit (DCB) (23.5% vs. 72.1%,p<0.001), progression-free survival (PFS) (3.76 vs. 14.40 months;p<0.001) and overall survival (OS) (12.20 vs. 44.84 months;p=0.008). Compared with PD-L1-negative patients, PD-L1-positive patients had a significantly higher objective response rate (ORR) (70.0% vs. 28.8%,p<0.001) and a prolonged mPFS (25.35 vs. 4.64 months,p=0.003) and tended to have an increased mOS (44.84 vs. 20.42 months,p=0.087). A signature comprising PD-L1<1% and the top 33% CXCL12 level was associated with the lowest ORR (27.3% vs. 73.7%,p<0.001) and DCB (27.3% vs. 73.7%,p<0.001) and the worst mPFS (2.44 vs. 25.35 months,p<0.001) and mOS (11.97 vs. 44.84 months,p=0.007). Area under the curve (AUC) analyses of PD-L1 expression, CXCL12 level and PD-L1 expression plus CXCL12 level to predict DCB or no durable benefit (NDB) showed AUC values of 0.680, 0.719 and 0.794, respectively.ConclusionOur findings suggest that serum cytokine CXCL12 levels can predict the outcomes of patients with NSCLC receiving ICI. Moreover, the combination of CXCL12 levels and PD-L1 status can predict outcomes with a significantly improved discriminatory power.