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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Circular RNAs (circRNAs) are increasingly recognized for their roles in cancer immunity.
• The specific function of circRNAs in the immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is not well understood.

Purpose of the Study:

• To identify and characterize novel circRNAs involved in PDAC immunosuppression.
• To elucidate the molecular mechanisms by which circSERINC3 contributes to immune evasion in PDAC.
• To evaluate circSERINC3 as a potential therapeutic target for PDAC immunotherapy.

Main Methods:

• Identification of circSERINC3 in PDAC tissues.
• Clinical correlation analysis of circSERINC3 expression with patient prognosis.
• In vitro and in vivo functional studies using cell lines and orthotopic mouse models.
• Assessment of T-cell cytotoxicity and cytokine secretion.
• Mechanistic studies involving protein complex stabilization, kinase activity assays, and pathway analysis.
• Pharmacological inhibition of CDK5.

Main Results:

• circSERINC3 was found to be upregulated in PDAC tissues and associated with poor patient prognosis.
• circSERINC3 suppressed CD8+ T-cell cytotoxicity and cytokine production.
• circSERINC3 stabilized a complex with CDK5 and STAT3, promoting STAT3 phosphorylation and PD-L1 upregulation.
• circSERINC3 promoted tumor growth and reduced survival in PDAC mouse models.
• CDK5 inhibition reversed circSERINC3-mediated immunosuppression and restored T-cell function.

Conclusions:

• circSERINC3 is a novel immunosuppressive circRNA in PDAC, driving immune evasion via the CDK5-STAT3-PD-L1 axis.
• circSERINC3 represents a promising therapeutic target for overcoming immunotherapy resistance in PDAC.