circSERINC3 facilitates STAT3-CDK5 crosstalk to orchestrate immunosuppressive microenvironments in pancreatic Cancer.

Circular RNAs (circRNAs) have emerged as critical regulators of tumor immunity, yet their role in orchestrating immunosuppressive microenvironments in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we identify circSERINC3 as a novel immunosuppressive circRNA upregulated in PDAC tissues. Clinical analysis reveals that high circSERINC3 expression correlates with advanced TNM stage, distant metastasis, and poor prognosis in PDAC patients. Functional studies demonstrate that circSERINC3 suppresses CD8+ T-cell cytotoxicity and cytokine secretion (TNF-α, IFN-γ) through stabilizing a cytoplasmic complex with cyclin-dependent kinase 5 (CDK5) and signal transducer and activator of transcription 3(STAT3). Mechanistically, circSERINC3 acts as a molecular scaffold to facilitate STAT3 Ser727 phosphorylation via CDK5 kinase activity, leading to programmed cell death 1 ligand 1(PD-L1) upregulation and JAK/STAT3 pathway activation. Genetic manipulation of circSERINC3 in orthotopic PDAC mouse models confirms its role in promoting tumor growth and reducing survival. Notably, pharmacological inhibition of CDK5 reverses circSERINC3-mediated immunosuppression and restores T-cell effector functions. These findings establish circSERINC3 as a key driver of immunosuppression in PDAC through the CDK5-STAT3-PD-L1 axis, highlighting its potential as a therapeutic target for immunotherapy-resistant PDAC.