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CSTF2 shortens polyA tail of CXCL10 and drives immune suppression in pancreatic cancer

ABSTRACT: Alternative cleavage and polyadenylation (APA) has gained increasing attention in cancer biology, yet its role in tumor immunotherapy resistance remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (CSTF2) in pancreatic ductal adenocarcinoma (PDAC) cells, an APA-related gene, as a novel suppressor of anti-tumor immunity. CSTF2 promotes tumor development by inhibiting the infiltration and function of TCRαβ+CD4–CD8–NK1.1– innate αβ T (iαβT) cells. Mechanistically, CSTF2 downregulates CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3' untranslated regions (3'UTR) of CXCL10 RNA, resulting in shortened PolyA tails and reduced RNA stability. Consequently, we identified Forsythoside B, a selective inhibitor of the RNA recognition motif (RRM) of CSTF2, effectively activates anti-tumor immunity and reverses immune checkpoint blockade (ICB) therapy resistance. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE271287 | GEO | 2025/05/29

REPOSITORIES: GEO

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CSTF2 shortens polyA tail of CXCL10 and drives immune suppression in pancreatic cancer

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