Molecular and immune-mediated resistance to antibody-drug conjugates in breast cancer
5 affiliations
- 1Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori
- 2Department of Experimental and Clinical Biomedical Sciences, University of Florence
- 3Pathology Unit, ARNAS Civico di Cristina Benfratelli Hospital
- 4Pathology Unit, ASST Cremona
- 5Oncology and Hematology-Oncology Department, University of Milan
Abstract
Antibody-drug conjugates (ADCs) have progressively advanced the conceptual framework of targeted oncology, evolving from a way to deliver chemotherapy selectively to tumor cells into drugs that also interact with the immune system to support their action. In breast cancer, the approval of several novel ADCs has transformed the therapeutic landscape across HER2-positive, HER2-low and triple-negative disease. Despite these advances, primary and acquired resistance remain the dominant clinical challenge. This narrative review classifies these resistance mechanisms, examining their interactions and therapeutic implications. We organize resistance along two highly interconnected domains. A molecular domain encompasses target antigen alterations, defective endolysosomal trafficking, payload efflux, and altered apoptotic thresholds. An immunological domain includes impaired Fc-mediated functions, escape from immunogenic cell death, and microenvironment-mediated immunosuppression. These domains frequently converge each other to drive clinical failure. Importantly, immune-mediated effects depend heavily on specific ADC constructs, and their clinical impact requires further validation. While routine assays currently assess baseline candidate markers, advancing rational therapeutic sequencing will require validated biomarkers capable of capturing dynamic processes, such as receptor trafficking or functional immune evasion.
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BibTeX
@article{mattana2026molecular,
title = {{Molecular and immune-mediated resistance to antibody-drug conjugates in breast cancer}},
author = {Alvise Mattana and Chiara Veronese and Julia Penitenti and Elettra Unti and Elena Varotti and Andrea Vingiani and Daniele Lorenzini and Roberto Boffi and Agnese Graziosi and Romano Danesi and Giancarlo Pruneri},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1927515},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927515/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Molecular and immune-mediated resistance to antibody-drug conjugates in breast cancer
AU - Alvise Mattana
AU - Chiara Veronese
AU - Julia Penitenti
AU - Elettra Unti
AU - Elena Varotti
AU - Andrea Vingiani
AU - Daniele Lorenzini
AU - Roberto Boffi
AU - Agnese Graziosi
AU - Romano Danesi
AU - Giancarlo Pruneri
PY - 2026
DA - 2026/10/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1927515
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1927515/full
AB - Antibody-drug conjugates (ADCs) have progressively advanced the conceptual framework of targeted oncology, evolving from a way to deliver chemotherapy selectively to tumor cells into drugs that also interact with the immune system to support their action. In breast cancer, the approval of several novel ADCs has transformed the therapeutic landscape across HER2-positive, HER2-low and triple-negative disease. Despite these advances, primary and acquired resistance remain the dominant clinical challenge. This narrative review classifies these resistance mechanisms, examining their interactions and therapeutic implications. We organize resistance along two highly interconnected domains. A molecular domain encompasses target antigen alterations, defective endolysosomal trafficking, payload efflux, and altered apoptotic thresholds. An immunological domain includes impaired Fc-mediated functions, escape from immunogenic cell death, and microenvironment-mediated immunosuppression. These domains frequently converge each other to drive clinical failure. Importantly, immune-mediated effects depend heavily on specific ADC constructs, and their clinical impact requires further validation. While routine assays currently assess baseline candidate markers, advancing rational therapeutic sequencing will require validated biomarkers capable of capturing dynamic processes, such as receptor trafficking or functional immune evasion.
SN - 1664-3224
ER -