Circular RNA-Mediated Tumor Immune Escape: Mechanistic Architecture and Nanomedicine-Enabled Therapeutic Reprogramming

Jan 31, 2026Critical reviews in oncology/hematology

How Circular RNA Helps Tumors Avoid the Immune System and New Nanomedicine Treatments to Overcome This

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Abstract

Circular RNAs (circRNAs) play critical roles in tumor immune escape through various mechanisms.

circRNAs regulate immune escape by sustaining PD-L1 expression and driving CD8⁺ T-cell exhaustion.
They promote the expansion of regulatory T cells and myeloid-derived suppressor cells while skewing macrophages toward immunosuppressive phenotypes.
Exosomal circRNAs spread immunosuppressive signals, contributing to therapy resistance and systemic immune dysfunction.
A subset of circRNAs can induce immune responses, such as ferroptosis and immunogenic cell death.
Advancements in nanomedicine allow for targeted silencing of oncogenic circRNAs and delivery of therapeutic circRNAs.
The combination of circRNA biology and nanotechnology may lead to new RNA-guided cancer immunotherapies.

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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.

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Circular RNA-Mediated Tumor Immune Escape: Mechanistic Architecture and Nanomedicine-Enabled Therapeutic Reprogramming

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