CELL INTELLIGENCE · 肿瘤细胞治疗研究

Limited intratumoral persistence and insufficient proliferative capacity severely restrict the efficacy of chimeric antigen receptor (CAR)-T cell therapies in solid tumors. Here, we demonstrated that DLL3-targeting CAR-T cells co-expressing a CD56 chimeric switch receptor (CSR) and incorporating parallel 4-1BB costimulatory signaling (DBB .CBB) effectively address these limitations. In preclinical small cell lung cancer (SCLC) models, DBB .CBB exhibited sustained tumor infiltration, prolonged persistence, and superior antitumor activity. Mechanistically, parallel 4-1BB signaling dynamically programed CAR-T cell fate by promoting early expansion and memory maintenance, driving a highly proliferative effector state at the intermediate stage, and delaying terminal exhaustion at the later stage, thereby sustaining in vivo persistence and enabling durable antitumor responses. Building upon the intratumoral T-cell pool established by DBB .CBB, subsequent DLL3 trispecific T-cell engager (TriTCE) administration synergistically enhanced tumor eradication by further boosting CD8+ T cell infiltration and overall activation while mitigating exhaustion and terminal differentiation. Collectively, these findings establish a clinically translatable combinatorial framework to enhance the efficacy and durability of CAR-T therapy in solid tumors.