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<p>Alternative cleavage and polyadenylation (APA) have gained increasing attention in cancer biology, yet its role in modulating anti-tumor immune response remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (<i>CSTF2</i>), an APA-related gene, as a pivotal suppressor of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDAC). <i>CSTF2</i> promotes tumor development by inhibiting the infiltration and cytotoxic immune cell recruitment function of TCRαβ<sup>+</sup>CD4<sup>−</sup>CD8<sup>−</sup>NK1.1<sup>−</sup> innate αβ T (iαβT) cells. Mechanistically, CSTF2 diminishes CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3’ untranslated regions of <i>CXCL10</i> RNA, resulting in shortened PolyA tails and compromised RNA stability. Furthermore, we identify Forsythoside B, a selective inhibitor targeting the RNA recognition motif of CSTF2, can effectively activate anti-tumor immunity and overcome resistance to immune checkpoint blockade (ICB) therapy. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.</p><p></p>

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CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer

  • 期刊论文

  • 发表日期：

    2025年2月19日

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  • Xiaowei He,
  • Ji Liu,
  • Yifan Zhou,
  • Sihan Zhao,
  • Ziming Chen,
  • Zilan Xu,
  • Chunling Xue,
  • Lingxing Zeng,
  • Shuang Liu,
  • Shaoqiu Liu,
  • Ruihong Bai,
  • Shaojia Wu,
  • Lisha Zhuang,
  • Mei Li,
  • Hongzhe Zhao,
  • Quanbo Zhou,
  • Dongxin Lin,
  • Jian Zheng,
  • Xudong Huang,
  • Jialiang Zhang

摘要

Alternative cleavage and polyadenylation (APA) have gained increasing attention in cancer biology, yet its role in modulating anti-tumor immune response remains largely unexplored. Here, we identify the cleavage stimulation factor 2 (CSTF2), an APA-related gene, as a pivotal suppressor of anti-tumor immunity in pancreatic ductal adenocarcinoma (PDAC). CSTF2 promotes tumor development by inhibiting the infiltration and cytotoxic immune cell recruitment function of TCRαβ+CD4−CD8−NK1.1− innate αβ T (iαβT) cells. Mechanistically, CSTF2 diminishes CXCL10 expression by promoting PolyA polymerase alpha (PAPα) binding to the 3’ untranslated regions of CXCL10 RNA, resulting in shortened PolyA tails and compromised RNA stability. Furthermore, we identify Forsythoside B, a selective inhibitor targeting the RNA recognition motif of CSTF2, can effectively activate anti-tumor immunity and overcome resistance to immune checkpoint blockade (ICB) therapy. Collectively, our findings unveil CSTF2 as a promising therapeutic target for sensitizing PDAC to ICB therapy.