CAR-T cell therapy for breast cancer: Current status and future perspective

Within the expanding therapeutic landscape for breast cancer (BC), metastatic breast cancer (MBC) remains virtually incurable and tend to develop resistance to conventional treatments ultimately leading to metastatic progression and death. Cellular immunotherapy (CI), particularly chimeric antigen receptor-engineered T (CAR-T) cells, has emerged as a promising approach for addressing this challenge. In the wake of their striking efficacy against hematological cancers, CAR-T cells have also been used where the clinical need is greatest - in patients with aggressive BCs. Unfortunately, current outcomes fall considerably short of replicating that success, primarily owing to the scarcity of tumor-specific antigens and the immunosuppressive microenvironment within BC. Herein, we provide an up-to-date overview of both preclinical and clinical data concerning the application of CAR-T cell therapy in BC. By surveying the existing literature, we discuss the prevailing constrains of this therapeutic approach and overview possible strategies to advance it in the context of breast malignancies. Possible approaches include employing synthetic biology to refine antigen targeting and mitigate off-target toxicity, utilizing logic-gated CAR constructs to enhance specificity, and leveraging armored CARs to remodel the tumor micro-environment. Temporal and spatial regulation of CAR-T cells using inducible gene switches and external triggers further improves safety and functionality. In addition, promoting T cell homing through chemokine receptor engineering and enhancing manufacturing processes with universal CAR platforms expand therapeutic applicability. These innovations not only address antigen escape and T cell exhaustion but also optimize the efficacy and safety profile of CAR-T cell therapy. We, therefore, outline a trajectory wherein CAR-T cells may evolve from a promising experimental approach to a standard modality in BC therapy.