Non-Coding RNAs in Cancer Liquid Biopsy: From Regulatory Networks to Functional Biomarkers for Precision Oncology.

Liquid biopsy is now an established component of precision oncology, and its clinical implementation to date has been led by cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) assays. These assays report genomic alterations, yet they may be limited by low tumor fraction, reduced shedding in early disease, and incomplete representation of dynamic tumor biology. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and emerging small or poorly annotated RNA species, provide a complementary layer because they can reflect regulatory programs, tissue injury, immune modulation, metastatic communication, and therapeutic pressure. This review explores circulating and extracellular vesicle (EV)-associated ncRNAs as functional readouts in cancer liquid biopsy. We discuss their biological origin, carrier state, biofluid context, clinical applications, analytical technologies, artificial intelligence (AI)-assisted integration, standardization barriers, and regulatory requirements. The technology discussion considers sequencing, targeted amplification, and emerging direct or polymerase chain reaction (PCR)-free strategies as complementary translational routes for reliable ncRNA measurement. We propose that ncRNAs should not be viewed as alternatives to ctDNA, but as potential functional biomarkers that can link tumor genotype, regulatory state, and clinical phenotype within integrated multi-analyte precision oncology.