Mechanism of Action, Clinical Applications, and Drug Resistance Challenges of HER2Targeted Antibody-

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Amplification, overexpression, and activating mutations of human epidermal growth factor receptor 2 (HER2) are key oncogenic drivers in multiple solid tumors. Antibody–drug conjugates (ADCs) have reshaped the treatment paradigm for HER2-altered tumors by integrating the targeting specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule cytotoxins. This review systematically summarizes the molecular design and mechanisms of action of HER2targeted ADCs, pivotal clinical evidence for approved agents, innovative strategies for nextgeneration ADCs, expansion across tumor types, toxicity profiles and comprehensive management, resistance mechanisms, and the exploration of combination therapies. It further provides an indepth discussion of the bottlenecks in clinical translation, including companion diagnostics, HER2 heterogeneity, and the standardization of testing. Drawing on the development experience of TROP2-targeted ADCs, this article also envisions future directions such as bispecific ADCs, immune synergies, local drug delivery, and sequential therapy combining ADCs with small-molecule inhibitors, aiming to provide a comprehensive framework for the precision treatment of HER2altered solid tumors.

• 1N44551022F959-4210.pdf