SMAD7 在 CAR-T 细胞中的表达改善实体瘤治疗的持久性与安全性

Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF- promotes cytokine synthesis via the NF- B pathway.

Here, we coexpressed SMAD7, a suppressor of TGF- signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF- -triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure.

Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.

Mechanistically, SMAD7 downregulated TGF- receptor I and abrogated the interplay between the TGF- and NF- B pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF- . SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.

Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.