CAR T cells engineered against LAG-3: Unleashing potency in the tumor microenvironment of breast cancer

Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematologic malignancies but faces significant challenges in solid tumors such as breast cancer. A primary obstacle is the immunosuppressive tumor microenvironment (TME), which drives T-cell exhaustion and limits therapeutic efficacy. Lymphocyte-activation gene 3 (LAG-3) is a key mediator of this exhaustion, suppressing antitumor immunity upon engagement with ligands such as MHC class II. This review examines the rationale for targeting the LAG-3 pathway to enhance CAR T cell potency within the breast cancer TME. We critically evaluate emerging bioengineering strategies designed to counteract LAG-3-mediated suppression, focusing on two complementary approaches: (1) armored CAR T cells engineered to secrete anti-LAG-3 antibody fragments locally within the TME, and (2) CAR T cells modified to express dominant-negative LAG-3 receptors or with LAG-3 genetically ablated, conferring intrinsic resistance to this inhibitory axis. By combining precise tumor recognition with localized or intrinsic checkpoint disruption, these next-generation therapies aim to enhance T-cell persistence, proliferative capacity, and cytotoxic function. Interrupting LAG-3 signaling represents a transformative strategy to reverse TME-driven immunosuppression, offering the potential for more durable clinical responses in breast cancer. Translating this promise into reality will require rigorous preclinical validation and innovative clinical trial designs.