Exosomal circular RNAs in the tumor immune microenvironment: From regulatory mechanisms to therapeutic opportunities and translational hurdles (Review)

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.