Exosomal CircGANAB promotes cancer progression and immunotherapy resistance by degrading interacting RNAs and limiting T cell infiltration in pancreatic ductal adenocarcinoma

AIMS: Circular RNAs (circRNAs) play important roles in cancer. However, their roles in pancreatic ductal adenocarcinoma (PDAC) progression and therapeutic resistance are underexplored. Here, we investigated the roles and diagnostic potential of circGANAB in PDAC. METHODS: The level of circGANAB was examined in PDAC cell lines, tumor tissues and serum exosomes. A receiver operating characteristic curve was constructed to evaluate the diagnostic performance of circGANAB. The oncogenic roles of circGANAB in PDAC tumor growth, metastasis, and immunotherapy resistance were studied in mouse tumor models. CircRNA-pulldown, followed by RNA sequencing, was performed to identify circGANAB-interacting RNAs. RNA stability assay was performed to investigate the roles of circGANAB in regulating its interacting RNAs. RESULTS: CircGANAB was upregulated in PDAC cell lines, primary tumors and was further upregulated in metastatic tumors, with a positive link to the tumor size and poor prognosis. CircGANAB promoted PDAC cell growth, ferroptosis resistance, and metastasis. Furthermore, circGANAB limited anti-PD-L1 immunotherapy efficacy by inhibiting CD4+ and CD8+ T cell infiltration. Mechanistically, circGANAB directly interacted with tumor suppressive lncRNAs GAS5, lncLDAH3, and TMEM51-AS1 and mRNAs IL-13 and IL-17D, resulting in RNA degradation. Additionally, serum exosomal circGANAB significantly increased with good diagnostic performance as a non-invasive biomarker. Exosome-mediated intratumoral transfer of the oncogenic circGANAB promoted PDAC progression. CONCLUSIONS: The upregulated circGANAB holds promising potential as a novel diagnostic biomarker in PDAC. CircGANAB promotes PDAC tumor growth, metastasis, and immunotherapy resistance through degrading interacting RNAs. These results highlight the significance of circRNAs in the tumor microenvironment and the circRNA-RNA interaction gene regulatory mechanisms underlying oncogenesis and tumor progression.