CAR-T cell therapy for pancreatic cancer: Translating emerging targets and dual-targeting strategies from solid tumors.
Pancreatic ductal adenocarcinoma (PDAC) is regarded as one of the most lethal malignancies, characterized by a poor prognosis and significant resistance to conventional treatments. Although Chimeric Antigen Receptor (CAR)-T cell therapy has been considered to be a revolutionary treatment for B-cell malignancies, its efficacy against solid tumors, including PDAC, has been limited. Nevertheless, after numerous tests pre-clinically and clinically, the acceptance of the first New Drug Application (NDA) for a CAR-T therapy in a solid tumor has sparked considerable hope and interest, which could further accelerate the field. Unlocking the full potential of CAR-T in PDAC requires overcoming significant hurdles, primarily the lack of ideal tumor-specific antigens and the profoundly immunosuppressive tumor microenvironment (TME). Given the shared expression of tumor-associated antigens (TAAs) across diverse solid tumors, this review analyzes promising solid tumor targets to identify candidates with high translational viability for PDAC. We summarize the latest clinical progress of CAR-T cell therapy, highlight emerging therapeutic targets, and explore innovative engineering strategies for developing potent, multi-targeted CAR constructs that are advancing toward future clinical application.