Advancing breast cancer treatment through dual targeting CAR T cell therapy.

Dual targeting chimeric antigen receptor (CAR) T cell therapy offers a next generation strategy to overcome the limitations of single antigen approaches in breast cancer, including antigen heterogeneity, immune escape, and the suppressive tumor microenvironment. This review summarizes current advances in vector design, comparing lentiviral, retroviral, and transposon platforms, and highlights key manufacturing challenges such as reduced transduction efficiency in dual scFv constructs (65–75% versus 92–98% for single target CAR T cells), prolonged vein to vein timelines (18–28 days), and increased production costs ($500,000–$700,000 per treatment). Safety considerations including cytokine release syndrome, neurotoxicity, and on target off tumor effects are discussed alongside the lack of predictive biomarkers for patient selection. The review further explores innovations in CAR engineering such as tandem and bicistronic configurations, logic gated SynNotch circuits, and affinity tuned costimulatory domains designed to enhance persistence and specificity. Advances in automated bioreactor systems, nonviral delivery methods, and AI guided manufacturing have improved scalability and cost efficiency. Integration with checkpoint inhibitors, oncolytic viruses, and stromal remodeling agents shows promise for overcoming tumor microenvironmental barriers, while single cell antigen profiling and circulating tumor DNA monitoring enable more personalized dual antigen targeting. Emerging frontiers such as in vivo CAR engineering provide additional opportunities to simplify manufacturing and expand accessibility. Finally, regulatory innovation, decentralized production, and value based reimbursement models are discussed as essential components for translating dual targeting CAR T cell therapy from experimental development to a clinically viable and economically sustainable treatment for breast cancer.