Circulating RNA as a Functional Component of Liquid Biopsy in Cancer: Concepts, Classification, and Clinical Applications.

Liquid biopsy has become an integral component of precision oncology, with circulating tumor DNA serving as the dominant analyte for genomic profiling and disease monitoring. However, DNA-based approaches are intrinsically limited in their ability to capture dynamic cellular states, functional adaptation, and tumor-host interactions. Circulating RNA has emerged as a complementary class of liquid biopsy biomarkers that reflects active transcriptional programs and systemic biological responses. In this review, we conceptualize circulating RNA as a liquid transcriptome and propose a structured classification framework based on physical carriers, RNA biotypes, and layers of biological interpretation. We describe how circulating RNA signals encode tissue-of-origin information, cell-state dynamics, and host immune responses, thereby enabling system-level insight into cancer biology beyond mutation-centric analyses. Recent large-scale profiling efforts and advances in extracellular RNA characterization further support the biological relevance and analytical feasibility of circulating RNA across diverse biofluids. We discuss emerging applications of circulating RNA across the cancer continuum, including early cancer detection and multi-cancer screening, tissue-of-origin inference, longitudinal monitoring of treatment response, detection of adaptive resistance, and immunotherapy stratification. In parallel, we critically examine key technical, analytical, and computational challenges that currently limit reproducibility and clinical translation, emphasizing the importance of standardized workflows, transparent reporting, and multi-center validation. Finally, we outline future directions for integrating circulating RNA with genomic and proteomic biomarkers, supported by advances in artificial intelligence and machine learning. Collectively, this review positions circulating RNA as a functionally informative and clinically promising component of next-generation liquid biopsy strategies in oncology.