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

Dec 7, 2025Translational oncology

Circular RNAs in cancer immunity: links to immune evasion, treatment resistance, and combined nanomedicine approaches

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mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Circular RNAs (circRNAs) are critical regulators of cancer immunology, influencing tumor immune escape through multiple mechanisms.

CircRNAs maintain PD-L1 stability by regulating its degradation and phosphorylation.
They are packaged into exosomes, influencing immune cells to promote T-cell dysfunction and immunosuppressive environments.
CircRNAs contribute to resistance against immune checkpoint inhibitors and conventional cancer therapies.
Targeting oncogenic circRNAs may restore drug sensitivity and enhance antitumor immunity.
Synthetic circRNAs can encode immunostimulatory factors, potentially remodeling the tumor immune microenvironment.

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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.

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

Abstract

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