CXCL12 expression is associated with T-bet abundance and longer survival in lung adenocarcinoma

Background The tissue immune context and clinical significance of CXCL12 in lung adenocarcinoma (LUAD) remain unresolved. We integrated transcriptomic and tissue analyses to characterize CXCL12-associated immune features and survival. Methods TCGA-LUAD analyses included 515 primary tumors and 502 patients with overall survival (OS) data. Institutional analyses included 180 LUAD tumors, with a four-marker multiplex immunofluorescence panel assessed in 51. The median normalized CXCL12 mean fluorescence intensity (MFI) cutoff of 22.5% defined the primary institutional survival comparison; 23.61% was the optimized sensitivity cutoff. A secondary exploratory analysis used GSE126044, comprising 16 non-small-cell lung cancer (NSCLC) patients, including five responders, with imbalanced specimen types. Results Tissue CXCL12 correlated with T-bet abundance (Spearman rho = 0.616; bootstrap 95% CI 0.419–0.754), with consistent leave-one-out estimates. Higher tissue CXCL12 was associated with longer OS under median grouping (log-rank P = 0.026). The Cox model, adjusted for age, sex, and stage, showed a favorable association (HR 0.94, 95% CI 0.89–0.99). TCGA analyses identified broad CXCL12-associated immune programs. After purity adjustment, the CXCL12–TBX21 association was essentially absent (partial rho = 0.024), and Th1 and cytotoxicity associations were no longer significant. TCGA survival associations were not robust across continuous-expression and median-split models. Conclusions Tissue CXCL12 is associated with T-bet abundance and longer OS in the institutional LUAD cohort. These findings support independent validation of CXCL12 as a candidate prognostic marker.