From molecular engineering to clinical applications: The expanding role of bispecific antibodies in onco-immunology

Bispecific antibodies (bsAbs) have emerged as one of the most versatile innovations in immunotherapy, capable of simultaneously engaging two distinct epitopes within a single molecule and thereby expanding the functional repertoire of conventional monoclonal antibodies. Their capacity to integrate checkpoint blockade, co- stimulatory activation and cytokine modulation renders them particularly attractive in conditions driven by dysregulated or redundant immune pathways, including cancer, autoimmunity, chronic inflammation and in- fectious diseases. Technological advances such as knobs-into-holes, dual-affinity retargeting (DART) constructs and IgG-like asymmetric designs have refined stability, pharmacokinetics and manufacturability, enabling clinical translation beyond oncology. Nevertheless, significant challenges remain, including immunogenicity, cytokine release syndrome, neurotoxicity and adaptive resistance mediated by antigen modulation or tissue microenvironmental adaptation. To mitigate these, innovative approaches, ranging from protease-activatable constructs and Fc engineering to albumin-binding fusion proteins and bispecific antibody–drug conjugates, are under active investigation. In addition, bsAbs are being integrated with other immunomodulatory strategies such as CAR-T cells, therapeutic vaccines and checkpoint inhibitors, offering the potential for synergistic benefit across diverse immune-mediated diseases. In this review, we chart the trajectory of bsAb development from molecular design to clinical translation in cancer and immune regulation. We highlight structural optimisation, pharmacokinetic tuning and mechanisms of immune regulation, aiming to provide a framework for their rational use in reshaping immune response in cancer and beyond.