Antibody–drug conjugates and immunogenic cell death in breast cancer: agent-specific mechanisms, clinical evidence and translational priorities
- 1Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine
Abstract
Antibody–drug conjugates (ADCs) and immune-checkpoint inhibitors (ICIs) are reshaping breast cancer treatment, but the extent to which individual ADCs induce immunogenic cell death (ICD) remains construct specific. Microtubule-inhibitor and topoisomerase I-inhibitor payloads can generate distinct forms of cellular stress and ICD-associated signals, including calreticulin (CALR) exposure, adenosine triphosphate (ATP) and high-mobility group box 1 (HMGB1) release, and type I interferon signalling. These molecular hallmarks indicate immunogenic potential but do not establish functional ICD without evidence of antigen-specific T-cell priming, immune-dependent tumour control or protective memory. Fc gamma receptor (FcγR)-mediated phagocytosis may facilitate antigen processing, whereas bystander killing primarily reflects payload diffusion and is not intrinsically immunostimulatory. Clinically, sacituzumab govitecan plus pembrolizumab improves progression-free survival over chemotherapy plus pembrolizumab in previously untreated programmed death-ligand 1 (PD-L1)-positive advanced triple-negative breast cancer, establishing the superiority of that treatment strategy without proving biological synergy or ICD-mediated benefit. This review integrates agent-specific preclinical evidence, breast cancer immune contexts, clinical trial data, resistance mechanisms and safety considerations. We propose an ADC–ICD competence framework comprising accessibility, danger signalling, immune reception and immune braking. The framework is intended to organise dynamic biomarker development and prospective validation, not to provide a numerical score or clinical decision rule.
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BibTeX
@article{fang2026antibodydrug,
title = {{Antibody–drug conjugates and immunogenic cell death in breast cancer: agent-specific mechanisms, clinical evidence and translational priorities}},
author = {Linghui Fang and Jialu Song and Xiaohui Wang and Fan Wang and Xiaotao Zhu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1978134},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978134/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antibody–drug conjugates and immunogenic cell death in breast cancer: agent-specific mechanisms, clinical evidence and translational priorities
AU - Linghui Fang
AU - Jialu Song
AU - Xiaohui Wang
AU - Fan Wang
AU - Xiaotao Zhu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1978134
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1978134/full
AB - Antibody–drug conjugates (ADCs) and immune-checkpoint inhibitors (ICIs) are reshaping breast cancer treatment, but the extent to which individual ADCs induce immunogenic cell death (ICD) remains construct specific. Microtubule-inhibitor and topoisomerase I-inhibitor payloads can generate distinct forms of cellular stress and ICD-associated signals, including calreticulin (CALR) exposure, adenosine triphosphate (ATP) and high-mobility group box 1 (HMGB1) release, and type I interferon signalling. These molecular hallmarks indicate immunogenic potential but do not establish functional ICD without evidence of antigen-specific T-cell priming, immune-dependent tumour control or protective memory. Fc gamma receptor (FcγR)-mediated phagocytosis may facilitate antigen processing, whereas bystander killing primarily reflects payload diffusion and is not intrinsically immunostimulatory. Clinically, sacituzumab govitecan plus pembrolizumab improves progression-free survival over chemotherapy plus pembrolizumab in previously untreated programmed death-ligand 1 (PD-L1)-positive advanced triple-negative breast cancer, establishing the superiority of that treatment strategy without proving biological synergy or ICD-mediated benefit. This review integrates agent-specific preclinical evidence, breast cancer immune contexts, clinical trial data, resistance mechanisms and safety considerations. We propose an ADC–ICD competence framework comprising accessibility, danger signalling, immune reception and immune braking. The framework is intended to organise dynamic biomarker development and prospective validation, not to provide a numerical score or clinical decision rule.
SN - 1664-3224
ER -