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

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 TCRaß+CD4–CD8–NK1.1– innate aß T (iaßT) cells. Mechanistically, CSTF2 downregulates CXCL10 expression by promoting PolyA polymerase alpha (PAPa) 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. Overall design: To evaluate the effects of Cstf2 KD on tumor microenvironment, we performed scRNA sequencing of tumor tissue from the KPC mice.