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

ABSTRACT: 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 inhi

SUBMITTER: Wu C 

PROVIDER: S-EPMC12804714 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature