Recent Advances and Future Challenges of Bispecific Antibodies in Lung Cancer

Bispecific antibodies (BsAbs) integrate two binding specificities to coordinate antitumor mechanisms that cannot be readily achieved with conventional monospecific antibodies. In lung cancer, these agents encompass four principal strategies: dual targeting of tumor-associated receptors, immune-cell redirection, simultaneous modulation of immune-regulatory pathways, and combined blockade of immune checkpoints and angiogenesis. This review synthesizes the molecular architectures, pharmacologic mechanisms, clinical development, safety profiles, and translational challenges of BsAbs in non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Clinical progress has been uneven. Randomized trials have established meaningful benefits for selected agents, exemplified by amivantamab-based therapy in EGFR-mutated NSCLC, ivonescimab-based therapy across several NSCLC settings, and DLL3-directed T-cell engagement with tarlatamab in previously treated SCLC. However, the failure of other biologically compelling constructs in phase III trials underscores that target pairing alone does not guarantee therapeutic synergy. Clinical outcomes are shaped by target density and co-expression, tumor dependence on the paired pathways, molecular format, tissue distribution, treatment setting, and patient selection. Toxicity is similarly mechanism specific and may include cytokine-release syndrome, neurotoxicity, epithelial and infusion-related events, immune-mediated injury, and vascular complications. Future development should move beyond empirical target combinations toward biomarker-guided patient selection, globally representative randomized validation, rational treatment sequencing, and molecular designs that increase tumor selectivity while preserving efficacy. Clinical value varies substantially among constructs and must be established in each disease setting.