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

Cell Death & Differentiation volume 32, pages 973–988 (2025)Cite this article

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Abstract

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.

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Fig. 1: Overexpressed CSTF2 in PDAC promoted poor prognosis dependent on immune.
Fig. 2: CSTF2 inhibits chemotaxis of CD8+ T, NK and iαβT cells to PDAC.
Fig. 3: CSTF2 inhibits recruitment of immune cells through down-regulating CXCL10.
Fig. 4: iαβT cells enhance the chemotaxis of cytotoxic CD8+ T and NK cells through CCL5.
Fig. 5: CSTF2 promotes PAPα adding shorter PolyA tails on CXCL10 pre-RNA.
Fig. 6: Targeting CSTF2 to enhance anti-tumor immunity sensitizes PDAC to the clinical ICB treatment.

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Data availability

The bulk RNA sequence data from 65 PDAC patients have been deposited in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics (BIG), Chinese Academy of Sciences http://bigd.big.ac.cn/ under restricted access: HRA000095. The data of Single-cell RNA-seq in this study have been deposited at Genome Sequence Archive (GSA) with accession numbers: GSE271287. The original contributions presented in the study are included in the article or the supplementary material.

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Acknowledgements

The authors would like to acknowledge Prof. Dongming Kuang (college of life science in Sun Yat-sen University) for his insightful advice during the project.

Funding

This study was supported by National Natural Science Foundation of China Projects (82325037 and 82072617 to J Zheng, 82272694 to X Huang, 82003162 to J Zhang, and 82303159 to CX), the National Key R&D Program of China (2021YFA1302100 to J Zheng), Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2017ZT07S096 to DL) and Cancer Innovative Research Programme of Sun Yat-sen University Cancer Center (CIRP-SYSUCC-0002 and PT13010201 to DL), Young Talents Programme of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0062 to J Zhang, YTP-SYSUCC0015 to J Zheng and YTP-SYSUCC-0068 to X Huang).

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Author notes

  1. These authors contributed equally: Xiaowei He, Ji Liu, Yifan Zhou, Sihan Zhao.

Authors and Affiliations

  1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China and Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China

    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, Hongzhe Zhao, Dongxin Lin, Jian Zheng, Xudong Huang & Jialiang Zhang

  2. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Mei Li

  3. Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China

    Quanbo Zhou

  4. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Dongxin Lin

  5. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China

    Dongxin Lin & Jian Zheng

  6. Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China

    Jian Zheng

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Contributions

X He, JL, J Zhang, J Zheng, DL and X Huang designed the study. X He, SZ and JL contributed to the performance of experiments, X He and YZ contributed to the interpretation of data. X He, J Zhang, J Zheng and DL contributed to the writing of the paper. ZC, ZX, CX, L Zeng, Shuang Liu, Shaoqiu Liu, RB and SW contributed to the methods and preparation of figure. L Zhuang, ML, HZ and QZ were responsible for tissue samples and matched clinical information collection. J Zhang, X Huang, J Zheng and DL supervised the work. For the co–first authors, the authorship order was assigned on the basis of their contributions to this work.

Corresponding authors

Correspondence to Jian Zheng, Xudong Huang or Jialiang Zhang.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from each patient, and this study was approved by the Institutional Review Board of the Sun Yat-sen University Cancer Center (approval number: GZR2020-036). All animal experiments were approved by the Institutional Animal Care and Use Committee of the Sun Yat-sen University Cancer Center (approval number: 2021-000284).

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He, X., Liu, J., Zhou, Y. et al. CSTF2-impeded innate αβ T cell infiltration and activation exacerbate immune evasion of pancreatic cancer. Cell Death Differ 32, 973–988 (2025). https://doi.org/10.1038/s41418-025-01464-0

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