From Immune Suppression to Immunotherapy Sensitization: The Dual Roles of circRNAs in Cancer Progression

Quan DaiXiaoli YuanHang DongHaiyi Xue^*

• Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Medicine & Laboratory of Translational Research in Ultrasound Theranostics, Chengdu, China

Circular RNAs (circRNAs) have recently emerged as critical regulators of tumor– immune interactions. Owing to their covalently closed structure, remarkable stability, and tissue-specific expression, circRNAs not only serve as molecular sponges and protein regulators but also play multifaceted roles in shaping the tumor immune microenvironment. Accumulating evidence indicates that circRNAs drive immune suppression by stabilizing PD-L1 through post-translational modifications and RNA-binding protein interactions, transmitting suppressive signals via exosomes to T cells and myeloid-derived suppressor cells, reprogramming glucose and lipid metabolism to deprive effector lymphocytes, and reinforcing cancer stemness and therapy resistance. In striking contrast, a subset of circRNAs has been shown to sensitize tumors to immunotherapy by activating innate immune pathways such as RIG-I/MAVS and STING, inducing immunogenic cell death, and overcoming resistance to endocrine therapy or ferroptosis inducers, thereby enhancing the efficacy of immune checkpoint blockade. Beyond their mechanistic functions, circRNAs also hold promise as stable and accessible biomarkers for prognosis, patient stratification, and therapeutic monitoring, particularly when enriched in circulating exosomes. Advances in antisense oligonucleotides, RNA interference, and nanomedicine provide new opportunities to therapeutically target oncogenic circRNAs or deliver engineered pro-immunogenic circRNAs. While significant challenges remain in detection accuracy, functional annotation, delivery specificity, and clinical validation, circRNAs represent a new frontier in immuno-oncology. Harnessing their dual roles may unlock innovative biomarker platforms and next-generation RNA-based therapeutics, ultimately improving the efficacy of cancer immunotherapy.