Zehao Ding, Zai Luo, Liao Zhang, Shaopeng Zhang, Renchao Zhang, Zhengjun Qiu, Chen Huang
Circular RNAs (circRNAs) are characterized by their covalently closed structure, remarkable stability, and precise spatiotemporal regulation, evolving from once-overlooked transcriptional byproducts to pivotal molecular regulators. In addition to their well-established function as microRNA sponges, circRNAs serve as protein scaffolds, transcriptional modulators, and even templates for functional peptide synthesis. This review synthesizes recent breakthroughs across the entire circRNA life cycle, encompassing biogenesis, degradation, nucleocytoplasmic transport, and extracellular vesicle-mediated secretion, while systematically analyzing their multifaceted involvement in tumorigenesis, immune evasion, metastatic dissemination, programmed cell death, and tumor-microbiome crosstalk. We highlight their exceptional potential as liquid biopsy biomarkers and critically assess translational applications in circRNA-based vaccines, targeted delivery platforms, and engineered cell therapies like CAR-T. Emerging artificial intelligence approaches that accelerate circRNA discovery, functional characterization, and therapeutic design are also discussed. Addressing current challenges in standardization and delivery methodologies, we propose future directions for incorporating circRNAs and their encoded proteins into precision oncology and next-generation immunotherapies. Together, these advances position circRNAs as a transformative paradigm with the potential to revolutionize cancer diagnostics, targeted therapeutics, and RNA vaccine development.