Emerging role of antibody-drug conjugates in gastrointestinal malignancies.

Gastrointestinal (GI) malignancies remain a major cause of global cancer-related mortality, especially in the setting of advanced or metastatic disease. Antibody-drug conjugates (ADCs) have emerged as a promising class of targeted therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Through advances in antibody engineering, linker chemistry, and payload design, modern ADCs have demonstrated enhanced efficacy with manageable toxicity. Therapeutic agents such as trastuzumab deruxtecan and disitamab vedotin are currently approved ADCs in HER2-overexpressing GI cancers, while multiple investigational ADCs targeting novel antigens, including Claudin 18.2, Claudin 6, B7-H3, c-MET, TROP2, and EGFR, are being evaluated in ongoing clinical trials.

Innovative designs-such as biparatopic and bispecific formats, dual or multipayload strategies, and the integration of novel cytotoxic modalities like radiotherapeutic agents-are under active development to address resistance mechanisms, optimize payload delivery, and minimize off-target toxicity. This review summarizes the structural components, mechanisms of action, approved agents, and evolving clinical pipeline of ADCs in GI cancers, highlighting both current challenges and emerging strategies aimed at expanding their therapeutic potential.