Circular RNA-mediated tumor immune escape: Mechanistic architecture and nanomedicine-enabled therapeutic reprogramming

Abstract

Circular RNAs (circRNAs) have emerged as pivotal regulators of tumor immune escape, acting through multilayered mechanisms that include miRNA sequestration, RNA-binding protein scaffolding, m⁶A-dependent stabilization, metabolic rewiring, and exosomal communication. These processes collectively sustain PD-L1 expression and stability, drive CD8⁺ T-cell exhaustion, promote Treg and MDSC expansion, skew macrophages toward immunosuppressive M2 phenotypes, and reshape glycolytic and lipid metabolic pathways to generate an immune-refractory microenvironment. In parallel, exosomal circRNAs disseminate long-range immunosuppressive signals, reinforcing therapy resistance and systemic immune dysfunction. Conversely, a newly recognized subset of “immune-activating circRNAs” induces ferroptosis, immunogenic cell death, and STING-mediated innate immune activation, highlighting the dual nature of circRNA immunoregulation. Recent advances in nanomedicine—spanning lipid nanoparticles, polymeric platforms, and biomimetic membrane-coated carriers—have enabled precise silencing of oncogenic circRNAs and efficient delivery of synthetic therapeutic circRNAs, demonstrating potent synergy with immune checkpoint inhibitors, NK-cell therapy, STING agonists, and ferroptosis inducers. Although challenges remain, including delivery specificity, biosafety, biomarker standardization, and off-target effects, the convergence of circRNA biology and advanced nanotechnology presents a transformative opportunity to develop next-generation RNA-guided cancer immunotherapies. Together, these findings position circRNAs as both key mechanistic drivers of immune escape and promising therapeutic targets for nanomedicine-enabled precision immunotherapy.