Topic: Mechanisms of Resistance and Management Strategies for Antibody–Drug Conjugates (ADCs) in Cancer
Guest Editor
Special Topic Introduction
Antibody–drug conjugates (ADCs) have become an important therapeutic class across multiple cancers, but primary and acquired resistance increasingly limit the depth and durability of benefit. Resistance can arise at every step of the ADC therapeutic pathway, including antigen loss or heterogeneity, impaired internalization and lysosomal trafficking, altered linker processing, drug efflux, payload-specific cross-resistance, enhanced DNA-damage repair, defective apoptosis, and changes in bystander activity. The tumor microenvironment may further shape response through stromal barriers, vascular delivery, immune-cell interactions, and adaptive survival signals. Although these mechanisms are increasingly recognized, the evidence remains fragmented across preclinical models, translational studies, and clinical observations.
This Special Topic will integrate mechanistic and clinical perspectives to establish a practical framework for understanding and overcoming ADC resistance. Priority areas will include resistance taxonomy, biomarker development, longitudinal tumor and liquid-biopsy analysis, functional models, rational sequencing, ADC rechallenge, payload switching, and combination strategies. The collection will also examine how next-generation targets, bispecific formats, novel linkers, alternative payloads, immune-stimulating conjugates, and improved trial designs may prevent or reverse resistance.
By connecting biological discovery with clinically actionable strategies to overcome resistance, this Special Topic aims to guide more durable and individualized use of ADCs across solid tumors and hematologic malignancies.
1. Target Biology, Binding, and Intracellular Processing
● Antigen expression, heterogeneity, and spatial distribution
● Target shedding, epitope alteration, and masking
● Internalization, endosomal routing, lysosomal function, and recycling
● Linker cleavage, payload release, and intracellular drug availability
● Bystander effect and resistance at tumor–normal tissue interfaces
2. Payload Resistance and Cell-Intrinsic SurvivalCross-resistance within and across payload classes
● Drug-efflux transporters and intracellular sequestration
● DNA-damage response and repair mechanisms
● Tubulin dynamics and resistance to microtubule-directed payloads
● Apoptotic threshold, senescence, quiescence, and lineage plasticity
● Clonal evolution under sequential ADC exposure
3. Tumor Microenvironment and Host Determinants of Resistance
● Stromal and extracellular-matrix barriers to ADC delivery
● Tumor vasculature, permeability, and intratumoral distribution
● Macrophage, lymphocyte, and fibroblast interactions
● Immune consequences of ADC-induced cell death
● Microenvironmental adaptation after prior chemotherapy, targeted therapy, or immunotherapy
● Pharmacokinetic, pharmacodynamic, and host factors affecting exposure
4. Biomarkers and Resistance Monitoring
● Tissue, blood, and imaging biomarkers
● Circulating tumor DNA and longitudinal molecular profiling
● Single-cell, spatial, proteomic, and functional approaches
● Quantitative assessment of target expression and heterogeneity
● Biomarkers of payload sensitivity and cross-resistance
● Integration of real-world data and artificial intelligence
5. Clinical Management of ADC Resistance, Sequencing, and Rechallenge
● Optimal sequencing of ADCs with shared or distinct payloads
● Clinical implications of target loss, target persistence, and target conversion
● ADC rechallenge and treatment beyond progression
● Management after resistance to HER2-, TROP2-, or other target-directed ADCs
● Disease-specific resistance patterns across breast, lung, gastrointestinal, gynecologic, genitourinary, and hematologic cancers
● Clinical decision-making when genomic or biomarker data are incomplete
6. Rational Combination Strategies
● ADCs with immune-checkpoint inhibitors
● ADCs with DNA-damage response inhibitors
● ADCs with targeted therapies, endocrine therapy, or antiangiogenic agents
● Strategies to modify antigen expression or intracellular trafficking
● Combinations designed to prevent resistance versus overcome established resistance
● Scheduling, dose optimization, overlapping toxicity, and patient selection
7. Next-Generation ADC Platforms to Overcome Resistance
● Novel targets and dual- or bispecific targeting
● Alternative payload classes and payload diversification
● Site-specific conjugation and optimized drug-to-antibody ratio
● Cleavable and non-cleavable linker innovation
● Probody, conditionally activated, and immune-stimulating conjugates
● Radioconjugates, degrader–antibody conjugates, and other emerging formats
● Preclinical models and trial designs capable of demonstrating resistance reversal
8. Translational Models and Resistance Clinical Trial Design
● Patient-derived models, organoids, and co-culture systems
● Functional precision oncology and ex vivo resistance testing
● Prospective collection of paired pre- and post-resistance specimens
● Window-of-opportunity and pharmacodynamic studies
● Endpoints that distinguish target failure from payload failure
● Basket, umbrella, and biomarker-enriched resistance trials
Submission Deadline
Submission Information
For Author Instructions, please refer to https://www.oaepublish.com/cdr/author_instructions
For Online Submission, please login at https://www.oaecenter.com/login?JournalId=cdr&IssueId=cdr26081910584
Submission Deadline: 30 Jun 2027
Contacts: Stella, Assisstant Editor, Stella@cdrjournal.net
