Dissecting non-small cell lung cancer (NSCLC) with blood proteomics—from surgical to immunotherapeutic responses

Abstract Objectives. Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with limited biomarkers to guide surgical and immunotherapeutic intervention. This study aimed to identify plasma proteomic signatures associated with surgical resection, recurrence, immunotherapy response, and survival by leveraging both high-plex and high-sensitivity proteomics technologies. Methods. Two complementary plasma proteomics platforms, SomaScan (quantifying 7596 proteins) and NULISAseq (quantifying 250 inflammation-related proteins), were used to profile the blood at 87 timepoints from 56 NSCLC patients. Samples were collected longitudinally: pre- and post-surgery (n = 20), pre- and post-immune checkpoint inhibitor (ICI) therapy (n = 11), and at baseline prior to ICI (n = 25). Proteomics data were analysed using adaptive Lasso regression (ALasso) and the Stabl algorithm for robust selection of a minimal number of differentially expressed proteins that collectively modelled the clinical classification or response. Results. We identified 21 differentially detectable plasma proteins across surgery and ICI treatment. Surgical resection induced measurable changes in plasma proteins, notably higher circulating MUC16 and lower circulating IL36G post-surgery in non-recurrent patients. Recurrent patients had higher plasma levels of COX7A2L, FGF19 and SPOCK2 post-surgery, and lower FCER2, FCRLA and SLITRK2. Patients who responded to ICI therapy had lower levels of baseline IL-6, CCL19, IL-2RA, CD200R1, CRP, LIF, PDCD1, CCL7 and SPP1 prior to ICI therapy, highlighting associations between systemic inflammation and immune regulation. CEACAM5, PTX3, FGF23, and AREG were elevated in patients with worse clinical outcomes and poorer overall survival. Cross-platform comparisons underscored the complementary strengths of SomaScan’s broad coverage and NULISA’s sensitivity in detecting low-abundance, clinically relevant proteins. Conclusions. This integrated plasma proteomics study reveals distinct protein signatures associated with NSCLC treatment response and prognosis. These findings support the utility of non-invasive, blood-based proteomic assays for defining biomarker discovery in NSCLC.