Evaluation of the Diagnostic and Prognostic Potential, and Correlation with the Tumor Immune Microenvironment of a Six-miRNA Signature Associated with Platinum Sensitivity in Patients with Early-Stage Non-Small-Cell Lung Cancer

Background/Objectives: Platinum-based chemotherapy remains a standard-of-care treatment for non-small-cell lung cancer (NSCLC), yet its efficacy is influenced by multiple factors, such as the functionality of DNA damage response pathways. DNA-damaging agents, like cisplatin, contribute to the generation of an “inflamed” tumor microenvironment (TME), which in turn correlates with an active antitumor immune response. MicroRNAs (miRNAs), a family of small, non-coding RNAs, have emerged as critical post-transcriptional regulators of gene expression, playing vital roles in modulating DNA Damage Repair (DDR) pathways and sensitivity to cisplatin. Their functional involvement in these mechanisms underscores their potential as diagnostic and prognostic biomarkers in lung cancer. Methods: In this study, we investigated the diagnostic and prognostic value of a previously validated six-miRNA signature (hsa-miR-26a, hsa-miR-29c, hsa-miR-34a, hsa-miR-30-5p, hsa-miR-30e-3p and hsa-miR-497) in paired tumor and healthy tissue samples from surgically treated NSCLC patients (n = 76), who later received platinum-based therapy. To explore the translational applicability of this signature, we also compared miRNA expression levels between matched tumor tissue and plasma samples (n = 36). We further examined the presence of an “inflamed” TME and its association with the miRNA signature by examining the mRNA levels of TIGIT, CD8A, FOXP3, CXCL10 and PD-L1, and performing correlation analysis. Results: All selected miRNAs were significantly downregulated in NSCLC tumor tissue compared to healthy samples. Moreover, miRNA expression was differentially regulated in plasma samples, supporting their potential clinical relevance as minimally invasive biomarkers. The complete six-miRNA signature demonstrated good discriminatory ability between tumor and matched non-malignant tissue (AUC = 0.786, 95% CI: 0.713–0.860; p < 0.001), with 72% sensitivity and 77.3% specificity. A significant correlation with relapse-free survival (RFS) (p = 0.039) was also observed. Distinct immune-related transcriptional alterations were observed in tumor tissue, including increased expression of immune checkpoint-associated genes (TIGIT and PD-L1) and reduced CD8A expression. Tumor PD-L1 expression showed modest positive correlations with miR-26a (p = 0.046) and miR-30e-3p (p = 0.031). Conclusions: Our findings underscore the potential value of this novel six-miRNA signature both as a prognostic and diagnostic biomarker in NSCLC. Its correlation with immune microenvironment characteristics supports its relevance in guiding personalized therapeutic strategies. This signature warrants further clinical validation and may serve as a valuable tool for patient stratification and outcome prediction for patients treated with platinum-based chemotherapy.