Harnessing microRNAs in lung cancer: The future of diagnosis and precision therapy

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death, driven by late diagnosis and therapeutic resistance. microRNAs (miRs) regulate post-transcriptional networks across cancer hallmarks and are unusually stable in biofluids, positioning them as powerful, minimally invasive biomarkers and therapeutic targets. This review summarizes current knowledge on miR biogenesis, regulation, and function in NSCLC; critically evaluates circulating and compartment-specific biomarkers (plasma/serum, sputum, and peripheral blood mononuclear cells (PBMCs); and appraises translational advances in oncomiR inhibition and tumor-suppressor restoration using modern delivery systems. We also analyze methodological progress, highlight persistent pre-analytical and normalization challenges, and outline practical routes toward regulatory-grade standardization. Convergent evidence indicates that circulating and exosomal miR panels can improve early detection and malignant-nodule triage, particularly when integrated with imaging and proteomic markers, and provide independent prognostic and treatment-monitoring value, often anticipating radiographic response or resistance. Despite strong pre-clinical efficacy, the clinical translation of miR mimics and inhibitors has been limited by delivery barriers and immunotoxicity, constraining progress into late-phase development. Unstandardized workflows and incomplete attribution of tumor-derived signals remain key barriers to clinical adoption. Overall, miRs hold strong potential to advance precision oncology in NSCLC through real-time disease monitoring and pathway-level targeting. Progress will likely depend on multimodal integration with circulating tumor DNA (ctDNA), proteomics, and imaging, alongside optimized delivery strategies, improved immunosafety, and rigorous multicenter validation to enable translation into routine care.