Cardiovascular biomarker phenotype associated with immune checkpoint inhibitor therapy in patients with non-small cell lung cancer: an exploratory blood transcriptome study

Background Immune checkpoint inhibitors (ICIs) have transformed the management of advanced non-small cell lung cancer (NSCLC), but their use is associated with potentially serious immune-related cardiotoxicity, often reflected by elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP). Identifying patients at risk before treatment initiation remains a major clinical challenge. The aim of this study was to investigate whether peripheral blood transcriptomic profiles are associated with susceptibility to an ICI-related cardiac biomarker-defined phenotype. Methods Peripheral blood RNA sequencing was performed in patients with advanced NSCLC receiving anti-PD-1/PD-L1 therapy (n=61) and in a control group with predominantly early-stage disease (n=29). Differential expression and functional enrichment analyses were used to characterize global and baseline transcriptomic differences, early treatment-related changes, and molecular signatures associated with NT-proBNP elevation and survival. Results Despite substantial transcriptomic overlap (86.0% of genes shared), global analysis revealed significant differences between early- and advanced-stage disease, as demonstrated by PCA and PERMANOVA. Baseline comparison in patients who subsequently developed NT-proBNP elevation identified a small set of differentially expressed genes (n=9), indicating subtle pre-treatment differences in regulatory and signaling pathways. Early response analysis demonstrated modest transcriptional changes after the first ICI cycle, with enrichment analyses pointing to immune-related pathways, including leukocyte migration and cytokine signaling. NT-proBNP-defined phenotype was associated with exploratory differential gene expression patterns and enrichment of pathways related to T-cell activation and immune signaling. Exploratory survival-associated transcriptomic profiles were characterized by enrichment of pathways related to platelet activation, coagulation and cell adhesion. Conclusion Peripheral blood transcriptomic profiling reveals stage-dependent and clinically relevant transcriptomic patterns in NSCLC, including early immune-related transcriptional changes and signatures associated with a cardiovascular biomarker phenotype defined by NT-proBNP changes. Although these alterations are subtle, they highlight the potential of peripheral blood transcriptomic profiling to identify transcriptomic signatures associated with an NT-proBNP-defined cardiovascular biomarker phenotype. Given the exploratory nature of the analyses and the relatively small size of several subgroups, particularly the survival comparison, these findings should be interpreted as hypothesis-generating and require validation in independent cohorts.