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<p>Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to its aggressive nature and limited treatment options, with the efficacy of immunotherapy constrained by a uniquely immunosuppressive tumor microenvironment (TME). In this study, we identify TNK2/ACK1 as a key regulator of the immunosuppressive TME in PDAC. TNK2/ACK1 is significantly upregulated in PDAC, at least in part via gene amplification and KRAS-G12 mutations. Mechanistically, TNK2/ACK1 directly phosphorylates and activates STAT5A to induce the expression of the immune checkpoint HVEM, which suppresses CD8⁺ T-cell function via its receptor BTLA. Pharmacologic targeting of TNK2/ACK1 with AIM100 or (R)−9b enhances CD8⁺ T-cell activation and cytotoxicity while reprogramming the TME. Furthermore, combining TNK2/ACK1 inhibitors with anti-PD-1 immunotherapy or with nab-paclitaxel plus gemcitabine demonstrates promising antitumor efficacy in both allograft and spontaneous PDAC models. Overall, our findings reveal a mechanism of immune evasion and provide a potential framework for developing tailored immunotherapeutic strategies in PDAC.</p>

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Targeting TNK2/ACK1 reverses the immunosuppressive tumor microenvironment and synergizes with immunochemotherapy in pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月6日

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  • Chao Wu,
  • Weishuai Liu,
  • Xiangting Hu,
  • Yongjie Xie,
  • Shengnan Li,
  • Xinyue Liu,
  • Zhaojun Sun,
  • Xiaoling Li,
  • Xin Yu,
  • Yudong Yuan,
  • Yiping Zou,
  • Ran An,
  • Yanan Chen,
  • Hailong Wang,
  • Yukuan Feng,
  • Song Gao,
  • Hongwei Wang,
  • Yifei Wang,
  • Nan Wang,
  • Chao Yang,
  • Jun Yu,
  • Peiqing Sun,
  • Chongbiao Huang,
  • Antao Chang,
  • Jihui Hao

摘要

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to its aggressive nature and limited treatment options, with the efficacy of immunotherapy constrained by a uniquely immunosuppressive tumor microenvironment (TME). In this study, we identify TNK2/ACK1 as a key regulator of the immunosuppressive TME in PDAC. TNK2/ACK1 is significantly upregulated in PDAC, at least in part via gene amplification and KRAS-G12 mutations. Mechanistically, TNK2/ACK1 directly phosphorylates and activates STAT5A to induce the expression of the immune checkpoint HVEM, which suppresses CD8⁺ T-cell function via its receptor BTLA. Pharmacologic targeting of TNK2/ACK1 with AIM100 or (R)−9b enhances CD8⁺ T-cell activation and cytotoxicity while reprogramming the TME. Furthermore, combining TNK2/ACK1 inhibitors with anti-PD-1 immunotherapy or with nab-paclitaxel plus gemcitabine demonstrates promising antitumor efficacy in both allograft and spontaneous PDAC models. Overall, our findings reveal a mechanism of immune evasion and provide a potential framework for developing tailored immunotherapeutic strategies in PDAC.