Homo sapiens Transcriptome or Gene expression
The clinical application of chimeric antigen receptor (CAR) T cell therapy in solid tumors remains limited due to significant safety concerns, particularly "on-target, off-tumor" toxicity and cytokine release syndrome (CRS). Here, we introduce novel CAR constructs employing disulfide-directed multicyclic peptides (DDMPs) as antigen-recognition domains, specifically targeting tumor-associated antigens HER2 and TROP2. Compared to traditional CAR constructs utilizing antibody-derived single-chain variable fragments, DDMP-based CARs greatly mitigated on-target, off-tumor toxicities. Furthermore, DDMP-based CAR T cells demonstrated robust antitumor efficacy in both in vitro and in vivo models, while secreting substantially lower cytokine levels, thereby minimizing the risk of CRS-related complications. These findings suggest that DDMP-based CAR constructs offer a promising strategy to enhance the safety and therapeutic potential of CAR T cell therapy for solid tumors.