Co‐Expression of Dominant‐Negative TGF‐β Receptor 2 Enhances the Therapeutic Efficacy of Novel TREM1/DAP12‐BB‐Based CAR‐T Cells in Solid Tumours

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.