EXPRESS: Circular RNAs as Next Generation Biomarkers for Minimal Residual Disease: Mechanistic Insights and Clinical Translation.
Minimal residual disease (MRD) denotes the persistence of malignant cells below the detection limits of conventional diagnostics and is a principal determinant of relapse and therapeutic failure. Enhancing MRD detection is therefore essential for precision oncology. Tumor‑derived circular RNAs (circRNAs)-covalently closed transcripts defined by back‑splice junctions-have emerged as compelling biomarkers for MRD owing to their exceptional stability, resistance to exonucleases, and enrichment in extracellular vesicles, which together enable reliable detection in biofluids. Beyond these analytical advantages, circRNAs actively participate in tumor biology through miRNA sponging, protein scaffolding, and transcriptional regulation, processes that contribute to epithelial-mesenchymal transition, therapy resistance, and metastatic competence. This review integrates current knowledge of circRNA biogenesis and molecular function, surveys cancer-type-specific circRNA expression signatures, and evaluates evidence for their utility in MRD monitoring across hematologic and solid malignancies. We propose multilayered diagnostic frameworks combining circRNA profiling with circulating tumor DNA (ctDNA), exosomal cargo analysis, and AI‑driven bioinformatics to improve sensitivity, specificity, and longitudinal risk stratification. Finally, we critically examine translational hurdles-preanalytical standardization, assay harmonization, cross‑platform reproducibility, clinical thresholding, and prospective validation-and outline strategic priorities to accelerate clinical implementation of circRNA‑based MRD surveillance for personalized patient management.