---
title: "Exosomal circular RNAs and their roles in the tumor immune microenvironment"
id: "pubmed-42757479"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42757479"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42757479/"
doi: "10.3892/ijmm.2026.5989"
published_at: "2026-09-18T12:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Exosomal circular RNAs and their roles in the tumor immune microenvironment
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42757479
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42757479/)
- **DOI:** [10.3892/ijmm.2026.5989](https://doi.org/10.3892%2Fijmm.2026.5989)
- **Published At:** 2026-09-18T12:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Immune checkpoint inhibitors have improved cancer therapy but durable responses remain limited because malignant, immune and stromal cells sustain immunosuppression in the **tumor immune microenvironment**. - **Extracellular vesicles (EVs)**, including small EVs, can carry and transfer **circular RNAs (circRNAs)** from donor to recipient cells, creating intercellular regulatory networks. - The pathway of interest spans circRNA biogenesis, loading into EV populations, delivery to recipient cells, intracellular activity, effects on immune phenotype and potential clinical applications. - Experimental distinctions matter: incomplete transfer experiments, tumor‑intrinsic circRNA activity and engineered RNA platforms are different from bona fide EV‑mediated transfer. - Direct EV transfer of circRNAs has been associated with modulation of multiple immune cell types, including **tumor‑associated macrophages**, **myeloid‑derived suppressor cells (MDSCs)**, **natural killer (NK) cells**, **CD8+ T cells** and **regulatory T cells (Tregs)**. - Within recipient cells, circRNAs can alter microRNA availability, assemble RNA‑binding protein complexes, change protein or RNA stability and even produce functional peptides. - Donor cell state, recipient identity, tissue site, EV subpopulation and delivered dose all influence the biological outcome of transferred circRNAs. - Cancer‑associated fibroblasts (CAFs) link EV‑associated circRNAs to matrix remodeling, immune‑cell access and therapy tolerance. - Evidence supporting biological transfer is classified from **E0 to E3**, while EV methodology must address source definition, separation, characterization, RNA protection, uptake controls and quantitative dosing. - Translation to biomarkers or therapeutics will require full‑length circRNA identification, absolute quantification in EVs and recipient cells, spatial localization, prospective treatment cohorts and repeated‑dose safety testing. - These requirements distinguish circulating associations from molecules actually transferred and identify experimental needs for development of EV‑circRNA biomarkers and therapies.
## Clinical Analysis & Structured Key Points
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Epub 2026 Sep 18. # Exosomal circular RNAs in the tumor immune microenvironment: From regulatory mechanisms to therapeutic opportunities and translational hurdles (Review) [Wenlong Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+W&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Nuo Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+N&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Liya Gong](https://pubmed.ncbi.nlm.nih.gov/?term=Gong+L&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Yu Dong](https://pubmed.ncbi.nlm.nih.gov/?term=Dong+Y&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Hui Shen](https://pubmed.ncbi.nlm.nih.gov/?term=Shen+H&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Xin Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+X&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Jie Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+J&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Luxuan Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+L&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Zhe Jin](https://pubmed.ncbi.nlm.nih.gov/?term=Jin+Z&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Liaoyuan Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+L&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Xue Han](https://pubmed.ncbi.nlm.nih.gov/?term=Han+X&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Bin Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+B&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Shuixing Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+S&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#full-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China.") Affiliations Expand ### Affiliation * 1 Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China. * PMID: **42757479** * DOI: [ 10.3892/ijmm.2026.5989 ](https://doi.org/10.3892/ijmm.2026.5989) Item in Clipboard Review # Exosomal circular RNAs in the tumor immune microenvironment: From regulatory mechanisms to therapeutic opportunities and translational hurdles (Review) Wenlong Zhang et al. Int J Mol Med. 2026 Nov. Show details Display options Display options Format Abstract PubMed PMID Int J Mol Med Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Int+J+Mol+Med%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Int+J+Mol+Med%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42757479/) . 2026 Nov;58(5):318. doi: 10.3892/ijmm.2026.5989. Epub 2026 Sep 18. ### Authors [Wenlong Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+W&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Nuo Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+N&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Liya Gong](https://pubmed.ncbi.nlm.nih.gov/?term=Gong+L&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Yu Dong](https://pubmed.ncbi.nlm.nih.gov/?term=Dong+Y&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Hui Shen](https://pubmed.ncbi.nlm.nih.gov/?term=Shen+H&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Xin Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+X&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Jie Sun](https://pubmed.ncbi.nlm.nih.gov/?term=Sun+J&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Luxuan Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+L&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Zhe Jin](https://pubmed.ncbi.nlm.nih.gov/?term=Jin+Z&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Liaoyuan Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+L&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Xue Han](https://pubmed.ncbi.nlm.nih.gov/?term=Han+X&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Bin Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+B&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China."), [Shuixing Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+S&cauthor_id=42757479)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42757479/#short-view-affiliation-1 "Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China.") ### Affiliation * 1 Department of Radiology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong 510630, P.R. China. * PMID: **42757479** * DOI: [ 10.3892/ijmm.2026.5989 ](https://doi.org/10.3892/ijmm.2026.5989) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID ## Abstract Immune checkpoint inhibitors have changed cancer treatment, although durable benefit remains limited because malignant, immune and stromal cells sustain suppression within the tumor immune microenvironment. Extracellular vesicles (EVs), including small EVs, can transfer circular RNAs (circRNAs) between defined donor and recipient cells. The relevant steps extend from circRNA biogenesis and entry into EV populations to delivery, intracellular activity, immune phenotype and clinical use. Incomplete transfer experiments, tumor‑intrinsic circRNA activity and engineered RNA platforms differ from direct EV‑mediated transfer. Direct transfer has been linked to tumor‑associated macrophages, myeloid‑derived suppressor cells, natural killer cells, CD8+ T cells and regulatory T cells. Within recipient cells, circRNAs can regulate microRNA availability, assemble RNA‑binding protein complexes, alter protein or RNA stability and produce functional peptides. Donor state, recipient identity, tissue site, EV subpopulation and delivered dose can change the resulting phenotype. Cancer‑associated fibroblasts further connect EV‑associated circRNAs with matrix remodeling, immune‑cell access and treatment tolerance. Biological support is classified from E0 to E3, while EV methods are considered separately through source definition, separation, characterization, RNA protection, uptake controls and quantitative dose. Translation will require full‑length circRNA identification, absolute measurement in EVs and recipient cells, spatial localization, prospective treatment cohorts and repeated‑dose safety testing. These requirements distinguish circulating associations from transferred molecules and identify the experiments needed for biomarker or therapeutic development. **Keywords:** cancer‑associated fibroblast; circular RNA; extracellular vesicle; immune checkpoint inhibitor; immune evasion; liquid biopsy; therapeutic resistance; tumor immune microenvironment. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Similar articles * [ Immunomodulatory behavior of CircRNAs in tumor microenvironment. ](https://pubmed.ncbi.nlm.nih.gov/40296917/) Liang H, Yan W, Liu Z, He Y, Hu J, Shu Z, Li H, Othmane B, Ren W, Quan C, Qiu D, Chen M, Xiong W, Zhang B, Liu P.Liang H, et al.Oncol Res. 2025 Apr 18;33(5):1105-1119. doi: 10.32604/or.2024.054623. eCollection 2025.Oncol Res. 2025.PMID: 40296917Free PMC article.Review. * [ Exosomal lncRNAs as molecular switches driving macrophage-tumor co-evolution in breast cancer. ](https://pubmed.ncbi.nlm.nih.gov/42218707/) Javadian M, Zeinali T, Rajabi M, Mehrasa Z, Boogari M, Ramezani F, Samaeinasab S, Mahmoudi Z, Hakimi H, Sabzehban R, Najafi K, Esmaeili K, Khaksarhaghani Z, Tahmasebi S, Rezaei R.Javadian M, et al.Clin Exp Med. 2026 May 31;26(1):288. doi: 10.1007/s10238-026-02199-z.Clin Exp Med. 2026.PMID: 42218707Free PMC article.Review. * [ Circular RNA-mediated tumor immune escape: Mechanistic architecture and nanomedicine-enabled therapeutic reprogramming. ](https://pubmed.ncbi.nlm.nih.gov/41619870/) Jiang S, Li Y, Wu D, Zhang L, Tian X, Meng F.Jiang S, et al.Crit Rev Oncol Hematol. 2026 Apr;220:105159. doi: 10.1016/j.critrevonc.2026.105159. Epub 2026 Jan 29.Crit Rev Oncol Hematol. 2026.PMID: 41619870Review. * [ Exosomal non-coding RNAs: orchestrators of intercellular crosstalk in the prostate cancer tumor microenvironment. ](https://pubmed.ncbi.nlm.nih.gov/41357241/) Duan H, Xu B, Luo P, Chen T, Zou J.Duan H, et al.Front Immunol. 2025 Nov 21;16:1644861. doi: 10.3389/fimmu.2025.1644861. eCollection 2025.Front Immunol. 2025.PMID: 41357241Free PMC article.Review. * [ The Potential Regulatory Roles of Circular RNAs in Tumor Immunology and Immunotherapy. ](https://pubmed.ncbi.nlm.nih.gov/33613544/) Fang Z, Jiang C, Li S.Fang Z, et al.Front Immunol. 2021 Feb 3;11:617583. doi: 10.3389/fimmu.2020.617583. eCollection 2020.Front Immunol. 2021.PMID: 33613544Free PMC article.Review. 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