Circular RNAs in cancer immunology: Immune escape, therapeutic resistance, and nanomedicine synergies

Circular RNAs (circRNAs), a class of covalently closed noncoding RNAs with remarkable stability and cell-type specificity, have emerged as critical regulators of cancer immunology. Increasing evidence reveals that circRNAs orchestrate tumor immune escape through multilayered mechanisms spanning post-transcriptional, post-translational, and metabolic levels, thereby reshaping the tumor immune microenvironment (TIME). A central theme involves the maintenance of PD-L1 homeostasis: circRNAs modulate PD-L1 stability via m^6A/IGF2BP-dependent RNA-protein interactions, protect PD-L1 from ubiquitin-mediated degradation through deubiquitinases, or promote its phosphorylation to prevent proteasomal turnover. Beyond tumor-intrinsic regulation, circRNAs are packaged into exosomes or small extracellular vesicles and delivered to immune cells, where they induce CD8^+ T-cell dysfunction, foster regulatory T-cell expansion, or reprogram myeloid-derived suppressor cells and macrophages toward immunosuppressive phenotypes. These intercellular communications contribute to resistance against immune checkpoint inhibitors and conventional therapies. In parallel, circRNAs are increasingly recognized as both therapeutic targets and agents. Strategies that silence oncogenic circRNAs using nanoparticles restore drug sensitivity and reinvigorate antitumor immunity, while synthetic or in vitro-transcribed circRNAs encoding immunostimulatory factors such as IL-12 demonstrate potent capacity to remodel TIME. The integration of tumor-tailored lipid nanoparticles, biomimetic vesicles, and rational circRNA design underscores a new wave of precision immunotherapy. This review highlights the mechanistic diversity of circRNAs in immune evasion, their roles in therapeutic resistance, and the translational opportunities offered by nanomedicine-based delivery systems. By bridging basic immunology and therapeutic innovation, circRNAs hold promise as next-generation targets and tools in cancer immunotherapy.