Co‐Expression of Dominant‐Negative <scp>TGF</scp>‐β Receptor 2 Enhances the Therapeutic Efficacy of Novel <scp>TREM1</scp>/<scp>DAP12</scp>‐<scp>BB</scp>‐Based <scp>CAR</scp>‐T Cells in Solid Tumours
Sichao Zhu, Jianping Hu, Jie Lin, Chen Wang, Enxiu Wang
Abstract
Chimeric antigen receptor (CAR) T-cell therapy has exhibited remarkable efficacy in the treatment of haematological malignancies, yet its application in solid tumours is hindered by the immunosuppressive tumour microenvironment (TME). In this study, a novel SS1-TREM1/DAP12-BB CAR-T cell was devised to target ovarian cancer and further engineered to co-express the dominant-negative TGF-β receptor 2 (DNR) to combat CAR-T cell exhaustion in TME. The incorporation of DNR effectively blocked TGF-β signalling, thereby enhancing CAR-T cell survival and antitumor activity in a TGF-β1-rich environment. In vivo evaluations demonstrated that DNR co-expression potentiated the antitumor efficacy of TREM1/DAP12-BB CAR-T cells and conferred resilience against tumour rechallenge. These findings underscore the broad potential of DNR co-expression in CAR design, presenting a novel therapeutic strategy for patients with recurrent ovarian cancer.