Work

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

Year: 2025

Type: article

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 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. Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, with treatment effectiveness, including immunotherapy, limited by immunosuppressive tumor microenvironment. This study identifies TNK2/ACK1 as a driver of immune evasion in pancreatic cancer via STAT5A-HVEM signaling that disables CD8⁺ T cells while TNK2 inhibition restores antitumor immunity and synergizes with anti-PD-1 and chemotherapy in PDAC models.

Source: Nature Communications

DOI: 10.1038/s41467-025-67197-3