Local radiotherapy polarized tumor-associated macrophages enhance the efficacy of Claudin18.2-targeted CAR-T therapy in pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and a 5-year survival rate of less than 10%. Its dense, immunosuppressive tumor microenvironment (TME) limits the effectiveness of conventional therapies, including immunotherapy. Chimeric antigen receptor T-cell (CAR-T) therapy targeting the tight junction protein claudin18.2 (CLDN18.2) has shown promise in preclinical PDAC studies, but its efficacy is severely constrained by immunosuppressive components in the TME, such as tumor-associated macrophages (TAMs). In addition to directly killing tumor cells, radiotherapy (RT) can modulate the TME, promote immune cell infiltration, and potentially enhance the efficacy of CAR-T in solid tumors. This study aimed to investigate the effects of combining RT with CLDN18.2-targeted CAR-T therapy for PDAC, focusing on elucidating whether RT can overcome the major barriers to immunotherapy in PDAC by reshaping the immunosuppressive TME and enhancing CAR-T infiltration and function. Methods: Second-generation anti-CLDN18.2 CAR-Ts with high transduction efficiency were generated. Results: Conclusions: Local RT significantly enhanced the anti-tumor efficacy of CLDN18.2-targeted CAR-T therapy against PDAC.