Functions and mechanisms of circular RNAs in cancer stem cells and therapy resistance

Cancer stem cells (CSCs) play a central role in tumor initiation, progression, recurrence, and therapy resistance. Their abilities for self-renewal, multi-lineage differentiation, and strong resistance make conventional chemotherapy, targeted therapy, and radiotherapy insufficient to completely eradicate tumors. In recent years, circular RNAs (circRNAs), a class of novel non-coding RNAs, have been shown to regulate CSC properties through multiple mechanisms, including acting as miRNA sponges, interacting with proteins, modulating signaling pathways, and encoding small peptides. Accumulating evidence indicates that circRNAs are aberrantly expressed in CSCs across various tumor types, including liver cancer, lung cancer, breast cancer, gastric cancer, prostate cancer, ovarian cancer, glioma, and acute myeloid leukemia, influencing stemness and drug sensitivity via specific signaling pathways or regulatory networks. CircRNAs have potential as biomarkers for diagnosis, prognosis, and therapy resistance prediction, as well as promising therapeutic targets. Strategies targeting oncogenic circRNAs, such as siRNA or shRNA delivered via liposomes, can effectively suppress CSC stemness and resistance and may be combined with chemotherapy, targeted therapy, or immunotherapy. Despite challenges such as incomplete mechanistic understanding, CSC heterogeneity, and limited clinical validation, advances in single-cell sequencing, circRNA interference, and nanocarrier delivery provide new opportunities for clinical translation. Overall, circRNAs play critical roles in maintaining CSC stemness, modulating drug resistance, and promoting tumor progression, offering novel avenues for overcoming therapy-resistant CSCs and for early diagnosis, prognosis assessment, and personalized treatment.