Converting TCR-based chimeric antigen receptor STAR into dual-specific targeting receptor for cancer immunotherapy.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved great success in treating hematopoietic malignancies; however, post-therapy relapse remains a challenge. Traditionally, multi-specific CAR engineering requires precise arrangement of single-chain variable fragments (scFvs), which can lead to aggregation issues when assembled linearly. In this study, we developed a novel chimeric receptor, the dual-targeting synthetic TCR and antigen receptor (D-STAR). D-STAR exhibited structural advantages, activating T cells and inducing effector functions in response to single antigen stimulation while mediating robust killing against various malignant B cells. In mouse models, D-STAR demonstrated superior antitumor efficacy compared to single- and dual-targeting CAR-T cells. To enhance its effectiveness, we integrated the OX40 costimulatory cytoplasmic domain with flexible linkers, boosting T cell proliferation and fitness under higher tumor burdens in vivo. This study illustrates the superior structural capacity and antitumor potency of D-STAR T cells.