Circulating MicroRNAs in non-small cell lung cancer: Clinical potential, analytic pitfalls, and barriers to implementation.

Background: Neoadjuvant chemoimmunotherapy is standard care for resectable non-small cell lung cancer (NSCLC), yet 70% to 80% of patients do not achieve a pathologic complete response, and no validated biomarker identifies likely non-responders before or during treatment. Circulating microRNAs (miRNAs) have been proposed as non-invasive prognostic and predictive biomarkers, but their value in this setting remains largely undefined. Main body: Prognostic associations exist for miR-21, let-7, and miR-34a, with the miR-200 family reported inconsistently, and emerging predictive value for chemotherapy and checkpoint inhibitor response. A five-miRNA whole-blood signature, miRisk, stratified overall survival in two immunotherapy cohorts (n = 195) and outperformed PD-L1 TPS in both. In a chemoimmunotherapy control cohort (n = 139), the association with survival was not significant, a dissociation consistent with immunotherapy-specific rather than purely prognostic value. miR-34a, the miR-200/141 cluster, and miR-197 regulate the PD-1/PD-L1 axis directly in tissue and preclinical models, providing a mechanistic basis for immunotherapy-specific prediction. Whereas circulating tumor DNA captures tumor genotype and burden, miRNAs may additionally reflect the functional state of tumor and immune interactions, on which chemoimmunotherapy response depends. Demonstrating this requires paired tissue and plasma measurement, which is lacking. In the neoadjuvant setting, evidence is limited to one small proof-of-concept study, leaving pathologic response prediction open. Translation is constrained by pre-analytical heterogeneity, the absence of a consensus normalization strategy, and the near-complete absence of prospective validation. Conclusion: Circulating miRNAs complement ctDNA, but their clinical potential remains unrealized. Closing this gap will require mechanistically selected multi-miRNA panels, measured serially, integrated with ctDNA, and tested in adequately powered studies that standardize methodology from the outset.