Plasma proteomics predicts pathological complete response and reveals LIF as a potential mediator of resistance to...

Neoadjuvant immunochemotherapy (nICT) is increasingly used for resectable non-small cell lung cancer (NSCLC), yet a substantial proportion of patients fail to achieve pathological complete response (pCR). Clinically scalable, minimally invasive biomarkers that predict response and point to actionable resistance mechanisms remain needed.

Pretreatment plasma samples collected prior to the first dose were profiled using the Olink proximity extension assay in a Sun Yat-sen University Cancer Center cohort (n=86), randomly split into a training set (n=65) and an internal validation set (n=21). Differentially abundant proteins associated with pCR were identified, and predictive models were developed using logistic regression, random forest, and extreme gradient boosting (XGBoost), followed by internal validation and independent external validation in the Jiangmen Central Hospital cohort (n=46). Survival associations were evaluated by Cox regression. Mechanistic analyses integrated tumor immunohistochemistry/multiplex immunofluorescence, bulk RNA sequencing with immune deconvolution, and functional validation in subcutaneous and orthotopic murine lung cancer models with pharmacologic leukemia inhibitory factor (LIF) blockade.

Four candidate proteins (LIF, CXCL1, CX3CL1, and NT-3) showed modest single-marker discrimination for pCR (area under the curve (AUC), 0.611-0.673). Multiprotein models improved prediction, with XGBoost achieving the highest performance (training AUC=0.95; internal validation AUC=0.845 (95% CI 0.65 to 1.00); external validation AUC=0.801 (95% CI, 0.57 to 0.93)). SHapley Additive exPlanations analysis identified LIF as the dominant feature negatively associated with pCR probability. Elevated baseline plasma LIF was associated with inferior overall survival (HR=13.003; 95% CI 1.456 to 116.135; p=0.0217) and progression-free survival (HR=3.75; 95% CI 1.362 to 10.327; p=0.0105) after nICT. High LIF tumors exhibited reduced CD8⁺ T-cell infiltration and suppressed cytotoxic effector programs. In murine models, LIF blockade synergized with immunochemotherapy to enhance antitumor efficacy, restore CD8⁺ T-cell effector function, and mitigate T-cell exhaustion.

Baseline plasma proteomics shows promise for predicting pCR to nICT in resectable NSCLC and nominates LIF as a predictive, prognostic, and therapeutic candidate mediator of resistance. These findings warrant prospective validation and further investigation of LIF-targeted combination strategies in the neoadjuvant setting.