T-cell bispecific antibodies (TCBs), a specialized subclass of bispecific antibodies (BsAbs), are engineered to simultaneously engage T cells and tumor cells by binding two distinct antigens—or two epitopes on a single antigen—thereby redirecting cytotoxic T lymphocytes to eliminate malignant cells. These agents enhance anti-tumor immunity through dual mechanisms: direct activation of T cell receptor (TCR)-mediated signaling and modulation of T cell function via immune checkpoint (ICP) pathways. Clinically, TCBs have demonstrated transformative efficacy, particularly in hematologic cancers, heralding a new era in tumor immunotherapy. Despite their therapeutic promise, widespread clinical adoption of TCBs is impeded by significant challenges—including severe immune-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), as well as resistance conferred by the immunosuppressive tumor microenvironment (TME). This review provides a comprehensive analysis of TCBs, encompassing their molecular design, mechanisms of action, and clinical performance across oncology indications. We systematically compare current TCB platforms with respect to therapeutic strategy, structural format selection, safety profiles, and clinical outcomes. Additionally, we critically evaluate the major translational hurdles facing TCB-based therapies and explore emerging solutions—including the development of novel format antibodies, rational combination regimens with immune checkpoint inhibitors or other immunomodulators, the application of artificial intelligence (AI) in de novo antibody design, and antibody drug conjugates (ADCs). In summary, this review not only highlights the current landscape and limitations of TCBs but also outlines actionable strategies to overcome existing barriers—serving as a valuable resource for researchers, clinicians, and biopharmaceutical developers striving to advance the next generation of T-cell redirecting therapies into clinical practice.
Jiao et al. (Mon,) studied this question.