Bispecific Antibodies in Cancer Immunotherapy: Mechanisms, Challenges, and Emerging Therapeutic Strategies

Bispecific antibodies (BsAbs) have emerged as a promising therapeutic strategy in cancer immunotherapy, enabling simultaneous targeting of two distinct antigens to redirect immune effector cells, block compensatory pathways, and modulate the tumor immune microenvironment (TIME). Hundreds of BsAbs are currently in clinical trials, among which immune cell engagers (ICEs) demonstrate substantial therapeutic potential by bridging tumor cells and effector cells to enhance cytotoxic activity. However, the clinical translation of BsAbs is hampered by heterogeneous therapeutic responses, immune-related adverse events (irAEs), drug resistance, and inherent immunogenicity. In this review, we systematically dissect the applications of BsAbs in tumor immunotherapy, focusing on rational target combinations, underlying immunological mechanisms, and clinical therapeutic potential, while critically evaluating the advantages and limitations of representative BsAb modalities. We aim to address a key unresolved question: why some BsAb regimens achieve durable clinical efficacy (e.g., blinatumomab in hematological malignancies), whereas others show limited activity in solid tumors (e.g., vanucizumab). Through comparative mechanistic analysis, we clarify the critical trade-offs among therapeutic efficacy, systemic toxicity, and immunosuppressive barriers within the tumor microenvironment. To mitigate these translational bottlenecks, we summarize cutting-edge engineering approaches-including trispecific antibodies, prodrug-conjugated BsAbs, and proteolysis-targeting chimeras (PROTACs) - that optimize the balance between anti-tumor potency and off-target toxicity. This review provides a conceptual framework for advancing the translational development of BsAbs and guiding the rational design of next-generation precision cancer immunotherapies.