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

In this study, we utilized spatial transcriptome analysis, genomic copy number variation mutation profiling, and single-cell sequencing to identify an abnormal overexpression of TNK2, which is inversely correlated with PDAC prognosis and the development of an immune-suppressive microenvironment. Previous research has hinted at TNK2's role in tumor progression and its correlation with patient survival in various cancers, yet its involvement in the PDAC immune microenvironment and resistance to immunotherapy remains unexplored. Our findings reveal that TNK2 overexpression influences the formation of an immunosuppressive microenvironment, as demonstrated by cell communication analysis and immune landscape profiling. Additionally, TNK2 phosphorylates and activates STAT5a at the Y694 site, resulting in the upregulation of immune checkpoint HVEM and the exhaustion of CD8+ T cells. Treatment with AIM100, which disrupts the TNK2-STAT5a-HVEM regulatory axis, markedly mitigates the immunosuppressive microenvironment and enhances sensitivity to PD-1 inhibitors and AG chemotherapy.