Abstract

Background Immunochemotherapy has become the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), yet response rates remain limited. Identifying reliable non-invasive biomarkers is crucial for predicting therapeutic benefit and enabling personalized treatment strategies. Methods In this prospective study, we enrolled 32 patients with unresectable locally advanced or metastatic NSCLC receiving tislelizumab combined with carboplatin and paclitaxel. Serum exosomes were isolated via ultracentrifugation before treatment initiation. Small RNA sequencing was performed to profile exosomal miRNA expression, with differential expression validated by quantitative RT-PCR. Patients were classified into clinical benefit (CB) and non-benefit (non-CB) groups based on RECIST 1.1 criteria after two treatment cycles. Results We identified 19 differentially expressed exosomal miRNAs between CB and non-CB patients. Seven miRNAs were significantly upregulated in the CB group and validated by RT-qPCR. Among these, miR-192-5p demonstrated the highest predictive accuracy with an AUC of 0.77 (95% CI: 0.543–0.917). Functional enrichment analysis revealed that target genes of these miRNAs were involved in key signaling pathways including MAPK and Ras signaling, as well as biological processes related to apoptosis and cell cycle regulation. Conclusion This study provides preliminary evidence that a panel of serum exosomal miRNAs, particularly miR-192-5p, may serve as non-invasive biomarkers associated with response to immunochemotherapy in advanced NSCLC. These hypothesis-generating findings warrant further validation in larger, independent cohorts to evaluate their potential utility in guiding treatment selection and patient stratification.