Drug resistance to antibody-drug conjugates: mechanisms, challenges, and perspectives

Sep 23, 2026

Uploaded by Ben

Antibody-drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics by combining target precision with potent cytotoxic effects from chemotherapeutic payloads. This review surveys ADC development, including structural and mechanistic foundations and analyses of ADCs achieving clinical success. Despite major advances, drug resistance remains a key barrier to broader use. The article details resistance mechanisms such as altered target antigens and intracellular trafficking dysfunctions, then proposes strategies including next-generation ADC design, improved linkers and payloads, combination therapy, and pathway co-targeting.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages32

Reading Time1 h 21 min

AccessFree to download

Introduction

ADC development and rationale

Mechanisms of drug resistance

Alterations in target antigens

Intracellular trafficking dysfunctions

Strategies to overcome resistance

Next-generation ADC design

Combination therapies

Multi-pathway targeting

Cancer Biol Med 2026. doi: 10.20892/j.issn.2095-3941.2025.0707 REVIEW Drug resistance to antibody-drug conjugates: mechanisms, challenges, and perspectives Yajing Liu 1,2*, Yuwei Liu 1,2*, Tingting Wu 1,2, Xiaoming Bai 1,2, Shuman Wang 1,2, Luyun Zhang 1,2, Zhiwen Fu 1,2, Chen Shi 1,2 1 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; 2 Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China | ABSTRACT | Antibody-drug conjugates (ADCs) have emerged as a transformative class of cancer therapeutics by combining the target precision of antibodies with the potent cytotoxic effects of chemotherapeutic agents. This unique approach aims to enhance the effectiveness of cancer treatment while minimizing systemic toxicity. This review provides a comprehensive overview of ADC development, starting with explorations of the structural and mechanistic foundations, and advancing to in-depth analyses of ADCs that have achieved clinical success. Despite remarkable progress, the development of drug resistance remains a significant barrier to broader clinical application. We discuss the mechanisms underlying resistance, including alterations in target antigens, disruptions in ADC | | --- | --- | | KEYWORDS | internalization, and dysfunctions of intracellular trafficking. To address these challenges, we propose several strategies, such as designing next-generation ADCs equipped with improved linkers and novel payloads, implementation of combination therapies, and simultaneous targeting of multiple pathways to circumvent resistance. In conclusion, this review highlights the critical need for innovative approaches in the evolving ADC landscape, aiming to overcome resistance mechanisms and fully harness the therapeutic promise of ADCs in cancer treatment.
Antibody-drug conjugates; drug resistance; combination strategies; cancer therapy | Introduction Over the past few decades, cancer therapy has undergone a remarkable transformation, shifting away from the traditional paradigm of cytotoxic chemotherapies towards more targeted and personalized approaches1-3. The advent of targeted therapies, such as small-molecule inhibitors and monoclonal antibodies, has revolutionized cancer treatment by selectively targeting specific molecular pathways or antigens overexpressed on tumor cells4-6. Furthermore, the emergence of immunotherapies, which harness the power of the patient’s immune system to combat cancer, has opened up new frontiers in cancer care7,8. Despite these advances, treating cancers remains challenging and there is a constant need for novel *These authors contributed equally to this work. Correspondence to: Zhiwen Fu and Chen Shi E-mail: [zhiwenfu@hust.edu.cn](zhiwenfu@hust.edu.cn) and [shichen@hust.edu.cn](shichen@hust.edu.cn) ORCID ID: [https://orcid.org/0000-0002-0635-1368](https://orcid.org/0000-0002-0635-1368) and [https://orcid](https://orcid). org/0000-0002-0041-5498 Received November 12, 2025; accepted February 23, 2026; published online April 6, 2026. Available [at www.cancerbiomed.org](at www.cancerbiomed.org) ©2026 The Authors. Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4 .0) therapeutic modalities. Antibody-drug conjugates (ADCs) represent a promising class of targeted therapies that combine the specificity of monoclonal antibodies with the high potency of cytotoxic payloads, offering a unique opportunity to enhance the therapeutic index and reduce off-target toxicity observed in conventional therapies9,10. Conceptually proposed more than a century ago by Paul Ehrlich as “magic bullets,”early ADC development was limited by insufficient linker stability, suboptimal target selection, and unacceptable toxicity11. The modern era of ADCs began in the late 1990s and early 2000s, and was driven by advances in antibody engineering, linker chemis

FAQs

Why are antibody-drug conjugates considered promising in cancer therapy?

ADCs combine the tumor-targeting specificity of monoclonal antibodies with the strong cytotoxic activity of chemotherapeutic payloads, improving the therapeutic index and reducing off-target toxicity.

What major challenge limits the broader clinical application of ADCs?

Drug resistance remains a significant barrier, undermining effectiveness and limiting longer-term clinical benefit.

What resistance mechanisms are discussed in the review?

The review discusses resistance involving changes in target antigens and disruptions of intracellular trafficking, which can impair ADC function inside cells.

Sep 23, 2026

Uploaded by Ben