PTK6 promotes ferroptosis resistance and CD8+ T cell exhaustion in pancreatic tumors via reprogramming glucose and lipid metabolism.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor associated with poor prognosis and high mortality. The distinct metabolic reprogramming of nutrients in PDAC fosters an immunosuppressive tumor immune microenvironment (TIME) and compromises the efficacy of immunotherapy. Protein tyrosine kinase 6 (PTK6) is highly expressed in multiple solid tumors and contains a short N-terminal region featuring an SH2 domain capable of lipid binding, suggesting its involvement in lipid metabolic reprogramming within the malignant tumor microenvironment. Using PTK6-knockout mouse models and lipidomic sequencing, we investigated how PTK6 drives metabolic dysregulation and immune effector exhaustion in pancreatic tumors. Our findings uncover a "dual driver" role for PTK6 in PDAC progression: While it enhances cancer cell resistance to ferroptosis by the reprogramming lipid metabolism, it also promotes CD8+ T cell exhaustion through upregulating PD-1 and Tim-3 expression, ultimately driving immunosuppression. In summary, these findings identify PTK6 as a potential biomarker in PDAC and reveal a previously unrecognized role of PTK6 in linking tumor lipid metabolism to CD8+ T cell exhaustion. These data suggest that PTK6 may represent a candidate mechanistic target for further therapeutic exploration.