Targeting TNK2/ACK1 reverses the immunosuppressive tumor microenvironment and synergizes with immunochemotherapy in pancreatic cancer
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.
Authors
- Chongbiao Huang (ORCID: https://orcid.org/0000-0001-9468-9168)
- Chao Wu (ORCID: https://orcid.org/0000-0002-2219-5203)
- Song Gao (ORCID: https://orcid.org/0000-0001-7427-6681)
- Xiangting Hu
- Peiqing Sun (ORCID: https://orcid.org/0000-0003-2255-6504)
- Yukuan Feng (ORCID: https://orcid.org/0009-0005-6497-0748)
- Yongjie Xie (ORCID: https://orcid.org/0009-0003-3595-0866)
- Jun Yu (ORCID: https://orcid.org/0000-0003-3435-6550)
- Weishuai Liu (ORCID: https://orcid.org/0000-0002-9549-5020)
- Yudong Yuan
- Yiping Zou (ORCID: https://orcid.org/0000-0001-7522-6088)
- Zhaojun Sun (ORCID: https://orcid.org/0000-0002-0931-4044)
- Antao Chang (ORCID: https://orcid.org/0000-0001-9442-619X)
- Jihui Hao (ORCID: https://orcid.org/0000-0002-1607-1730)
- Xiaoling Li (ORCID: https://orcid.org/0009-0003-7903-9708)
- Ran An (ORCID: https://orcid.org/0009-0007-9123-1128)
- Nan Wang (ORCID: https://orcid.org/0000-0001-9318-0079)
- Shengnan Li (ORCID: https://orcid.org/0000-0002-3458-218X)
- Yifei Wang (ORCID: https://orcid.org/0000-0002-9918-2865)
- Hailong Wang (ORCID: https://orcid.org/0000-0002-8142-8521)
- Xin Yu
- Yanan Chen (ORCID: https://orcid.org/0000-0001-5510-231X)
- Xinyue Liu (ORCID: https://orcid.org/0009-0002-3299-0806)
- Chao Yang (ORCID: https://orcid.org/0000-0003-3422-2763)
- Hongwei Wang (ORCID: https://orcid.org/0000-0001-8198-0677)
Institutions
- Atrium Health Wake Forest Baptist (US)
- Sun Yat-sen University (CN)
- Nankai University (CN)
- Tianjin Medical University Cancer Institute and Hospital (CN)
- Translational Research in Oncology (FR)
- Fifth Affiliated Hospital of Sun Yat-sen University (CN)
- Cagayan State University (PH)
- Children's Hospital of Chongqing Medical University (CN)
- Wake Forest Baptist Comprehensive Cancer Center
- Wake Forest University (US)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-06
- DOI
- https://doi.org/10.1038/s41467-025-67197-3
- Citations
- 1
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.05