Review Finds Stable Circular RNAs as Noninvasive Biomarkers for Cancer Detection

Circular RNAs (circRNAs) are gaining momentum as viral-worthy candidates in the liquid biopsy revolution. Unlike linear RNAs, circRNAs form covalently closed loops that resist exonuclease degradation, preserving their integrity in blood and other clinical fluids. Because many circRNAs show tumor-associated expression patterns, their detectability offers a practical route to sensing cancer activity without invasive sampling.

A new review in Chinese Medical Journal synthesizes how circulating circRNAs could transform oncology across three frontiers: early detection, patient prognosis, and therapy monitoring. It also frames circRNAs not only as passive indicators, but as active biological regulators and, potentially, direct therapeutic targets.

Stability is the foundation. circRNAs persist in peripheral circulation and can be measured from specimens that extend beyond serum, including saliva, urine, cerebrospinal fluid, gastric juice, and platelet-derived material. This broadened sampling window could improve feasibility for repeated monitoring during cancer trajectories.

The review highlights the biological versatility of circRNAs in cancer. While circRNAs are often discussed as microRNA (miRNA) sponges that sequester miRNAs and alter downstream mRNA stability or translation, they can also bind proteins, influence alternative splicing of precursor mRNAs, and modulate epigenetic marks. In some contexts, circRNAs act as scaffolds that organize protein–protein interactions or function as decoys that re-route protein activity.

These mechanisms connect circRNAs to major cancer hallmarks, from sustained proliferation and metabolic reprogramming to immune evasion and drug resistance. Importantly, their levels may shift with tumor stage and correlate with clinically relevant events such as metastasis, enabling dynamic risk stratification.

For early diagnosis, the review emphasizes that diagnostic panels—rather than single biomarkers—can reach high performance, including in early-stage disease. Because circRNA signatures can reflect tumor evolution, they may serve as near real-time readouts of disease state.

Therapeutic monitoring is another key theme. Changes in circulating circRNA profiles may signal treatment response or emerging resistance, positioning circRNAs as functional drivers that could be therapeutically disrupted rather than merely measured.

The authors also address translational bottlenecks: standardizing sample handling, improving reproducibility, validating candidate panels in large prospective cohorts, and upgrading detection technologies. Approaches such as nanopore sequencing, droplet digital PCR, and CRISPR-based assays are discussed as potential enablers of clinical-grade performance.

Looking ahead, the review envisions a “circRNA-centric oncology” model in which endogenous circRNAs guide continuous tumor surveillance, while engineered circRNAs and related interventions offer programmable, pathway-targeted therapeutics.

Reference is available at DOI: 10.1097/CM9.0000000000004120.