Circular RNAs in cancer: from biomarkers to vaccine-based immunotherapy
Abstract
Circular RNAs (circRNAs) are endogenous, covalently closed RNA molecules generated through back-splicing that exhibit exceptional stability, evolutionary conservation, tissue-specific expression and diverse regulatory functions. Compared with conventional RNA-based therapeutic platforms, such as messenger RNAs (mRNAs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), circRNAs offer enhanced resistance to exonuclease-mediated degradation, prolonged intracellular persistence, and sustained protein expression. These characteristics have positioned circRNAs as promising candidates for cancer biomarkers and next-generation therapeutic platforms. Recent evidence indicates that they regulate multiple biological processes associated with tumour initiation and progression, including transcriptional regulation, miRNA sequestration, RNA-binding protein modulation, alternative splicing, cap-independent translation, immune signalling, and therapeutic resistance. Through interactions with innate and adaptive immune pathways, circRNAs regulate antigen presentation, cytokine production, immune-cell activation and tumour immune evasion, highlighting their importance in cancer immunotherapy. This review summarizes recent advances in circRNA biogenesis and their roles in cancer progression, therapeutic resistance, and immune regulation, with particular emphasis on engineered circRNAs as platforms for cancer vaccines and precision immunotherapy. We discuss advances in circRNA vaccine design, delivery, neoantigen targeting, biomarkers, and clinical translation, while highlighting key challenges including manufacturing, immunogenicity, tumor heterogeneity, regulatory requirements, and limited clinical validation. Overall, circRNAs represent a promising and versatile platform for cancer immunotherapy, with continued advances in RNA engineering, personalized neoantigen design, targeted delivery, and clinical evaluation expected to determine their potential for translation into effective and durable cancer treatments.