Investigating the role of costimulatory domains in enhancing CAR-T cell persistence in TNBC.

This work summarizes how costimulatory domains can mediate the persistence, function, and therapeutic potential of CAR-T cells in triple-negative breast cancer (TNBC), a highly aggressive malignancy with limited treatment options and an immunosuppressive tumor microenvironment. Although CAR-T cell therapy has produced remarkable results in hematologic malignancies, its translation to TNBC remains limited by poor T cell persistence, metabolic dysfunction, and rapid exhaustion. Current evidence identifies canonical costimulatory domains (CD28 and 4-1BB) as having differential effects on intracellular signaling, metabolic programming, and T cell differentiation; CD28-based CAR-T cells promote rapid activation and glycolytic metabolism but are commonly associated with terminal differentiation and decreased durability, whereas 4-1BB signaling supports mitochondrial fitness, oxidative phosphorylation, and the development of memory-like T cells that support longer-lasting persistence. The functional differences in CAR-T cells are context-dependent and influenced by antigen density, hypoxia, and other immunosuppressive signals within the TNBC tumor microenvironment. Newer costimulatory domains, such as HVEM and TNFRSF9, have added an additional layer of complexity to T cell signaling by modulating activating and inhibitory pathways, and their incorporation into CAR designs offers new ways to optimally regulate T cell responses; however, their functions are not fully defined in TNBC models. Additionally, dual costimulation strategies and combination therapies (metabolic reprogramming of T cells, epigenetic modulation, and immune checkpoint blockade) have shown promise in preclinical studies, but their translational value remains to be validated. An important message arising from this review is that while persistence may be improved through enhanced costimulatory signaling, the ideal performance of CAR T therapy occurs with the establishment of an ideal balance of stimulating signals that promote the sustained function of effector T cells while inhibiting the exhaustion of T cells and avoiding the deleterious effects of tonic activation. Furthermore, it is critical to evaluate data from TNBC models compared to other solid tumors to inform rational CAR T design strategies in TNBC.