Antibody-Drug Conjugates in Oncology: Mechanisms, Clinical Progress, and Future Directions

Zichun Zhu; Siwei Wang; Weifeng Hong; Qingping Zhong; Weixin Wang; Nan Wang; Minghua Bai; Ji Zhu

doi:10.66505/cbtt.v1i2.32

Authors

Zichun Zhu Wenzhou Medical University, Wenzhou, Zhejiang, China;Department of Radiation Oncology, Zhejiang Cancer Hospital; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences; Zhejiang Key Laboratory of Particle Radiotherapy Equipment, Hangzhou, Zhejiang, China
Siwei Wang Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Zhongshan Hospital, Liver Cancer Institute, Fudan University, Shanghai, China
Weifeng Hong Department of Radiation Oncology, Zhejiang Cancer Hospital; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences; Zhejiang Key Laboratory of Particle Radiotherapy Equipment, Hangzhou, Zhejiang, China
Qingping Zhong Wenzhou Medical University, Wenzhou, Zhejiang, China;Department of Radiation Oncology, Zhejiang Cancer Hospital; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences; Zhejiang Key Laboratory of Particle Radiotherapy Equipment, Hangzhou, Zhejiang, China
Weixin Wang Cosmos Wisdom biotech co. ltd，Building 10th, No. 617 Jiner Road, Hangzhou, 311215, China;Zhejiang Engineering Research Center for Intelligent Manufacturing of Clinical Diagnostic Equipment, Hangzhou, 311215, China
Nan Wang Cosmos Wisdom biotech co. ltd，Building 10th, No. 617 Jiner Road, Hangzhou, 311215, China;Zhejiang Engineering Research Center for Intelligent Manufacturing of Clinical Diagnostic Equipment, Hangzhou, 311215, China
Minghua Bai Department of Radiation Oncology, Zhejiang Cancer Hospital; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences; Zhejiang Key Laboratory of Particle Radiotherapy Equipment, Hangzhou, Zhejiang, China
Ji Zhu Wenzhou Medical University, Wenzhou, Zhejiang, China;Department of Radiation Oncology, Zhejiang Cancer Hospital; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences; Zhejiang Key Laboratory of Particle Radiotherapy Equipment, Hangzhou, Zhejiang, China

DOI:

https://doi.org/10.66505/cbtt.v1i2.32

Keywords:

antibody-drug conjugates, ADC, linker design, immunogenic cell death, ICD, Tumor microenvironment, targeted therapy, translational oncology

Abstract

Antibody-drug conjugates (ADCs) are a rapidly evolving therapeutic modality that integrates the target specificity of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs, thereby redefining precision oncology. By enabling selective delivery of highly toxic payloads to malignant cells, ADCs aim to maximize antitumor efficacy while limiting systemic toxicity. This review provides a comprehensive overview of ADC development, focusing on the rational design and functional interplay of the four core components: tumor-associated antigens, antibody scaffolds, linker chemistries, and cytotoxic payloads. Key considerations in target selection, antibody isotype choice, linker stability and cleavage mechanisms, and payload potency are discussed in detail. In addition, we summarize the principal in vivo mechanisms underlying ADC activity, including canonical intracellular payload release, bystander killing, antibody-mediated immune effector functions, and immunogenic cell death. These mechanisms collectively contribute to therapeutic efficacy, particularly in heterogeneous and treatment-resistant tumors. The review also provides an updated overview of 19 antibody-drug conjugates that have received regulatory approval worldwide, highlighting their clinical indications, linker-payload combinations, and representative efficacy outcomes. Safety profiles and treatment-related toxicities are examined, with emphasis on class-specific adverse events and tolerability considerations observed in clinical practice. Finally, we discuss emerging strategies and unresolved challenges in ADC development, including resistance mechanisms, linker-payload optimization, novel target discovery, and integration with immunotherapy and combination regimens. By synthesizing current clinical progress with mechanistic and technological insights, this review serves as a comprehensive reference to support future preclinical research, clinical trial design, and the rational advancement of next-generation ADC-based cancer therapies.

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