Bispecific antibodies in gastrointestinal cancers: current applications and future perspectives

Abstract

Gastrointestinal (GI) cancers remain a leading cause of cancer-related morbidity and mortality worldwide despite major advances in systemic therapy. Although immune checkpoint inhibitors have improved outcomes in selected biomarker-defined populations, most GI malignancies, including microsatellite-stable colorectal cancer, pancreatic ductal adenocarcinoma, and many biliary tract tumors, remain largely resistant because of low tumor immunogenicity, stromal exclusion, immune suppression, and adaptive resistance mechanisms. Bispecific antibodies (BsAbs) have emerged as a rapidly expanding class of immunotherapeutics capable of simultaneously engaging two distinct targets, enabling mechanisms such as T-cell redirection, dual checkpoint inhibition, combined immune and anti-angiogenic modulation, tumor-selective co-stimulation, and stromal remodeling. Recent clinical advances, including the approval of HER2-targeted zanidatamab and the emergence of multiple late-phase studies across GI malignancies, have validated the therapeutic potential of this platform. This review examines the biological rationale, structural formats, and mechanisms of action of BsAbs and summarizes current clinical evidence across colorectal, gastric, gastroesophageal, hepatocellular, pancreatic, biliary tract, esophageal, and neuroendocrine cancers. We also discuss emerging therapeutic targets, biomarker-driven patient selection, safety considerations, combination strategies, manufacturing challenges, and future directions. Collectively, current evidence suggests that BsAbs are poised to become an increasingly important component of precision immunotherapy, with the potential to overcome key limitations of conventional immunotherapeutic approaches in GI oncology.