CircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.

Background: Glioblastoma stem cells (GSCs) and their exosomes (exos) are involved in shaping the immune microenvironment, which is important for tumor invasion and recurrence. However, studies involving GSC-derived exosomal circular RNAs (GDE-circRNAs) in regulating tumor microenvironment (TME) remain unknown. Here, we comprehensively evaluated the significance of a novel immune-related GDE-circRNA in glioma microenvironment.

Methods: GDE-circPRKD3 was screened out through high-throughput sequencing and verified by RT-PCR, sanger sequencing and RNase R assays. A series of in vitro and in vivo experiments were performed to investigate the function of GDE-circPRKD3. RNA-seq, RNA immunoprecipitation, multicolor flow cytometry and western blotting were used to explore the regulation of GDE-circPRKD3 on STAT3 signaling-mediated TME remodeling.

Results: We have characterized a circRNA PRKD3 in GSC exosomes, and lower circPRKD3 expression predicts a worse prognosis for glioblastoma patients. Overexpression of GDE-circPRKD3 significantly impairs the biological competence of glioma and prolongs the survival of xenograft mice. GDE-circPRKD3 binds to HNRNPC in an m6A-dependent manner, accelerates mRNA decay of IL6ST and inhibits downstream target STAT3. Notably, GDE-circPRKD3 promotes CXCL10 secretion by reprogramming tumor-associated macrophages, which in turn recruits CD8+ tumor infiltrating lymphocytes against GBM. Moreover, brain-targeted lipid nanoparticle delivery of circPRKD3 combined with immune checkpoint blockade therapy achieves significant combinatorial benefits.

Conclusion: This study provides a novel mechanism by which GDE-circPRKD3 relies on STAT3 signaling to remodel immunosuppressive TME and offers a potential RNA immunotherapy strategy for GBM treatment.