Antibody–drug conjugates and immunogenic cell death in breast cancer: agent-specific mechanisms, clinical evidence and translational priorities
Year: 2026
Type: review
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.
Source: Frontiers in Immunology
Institution: Zhejiang University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7223184285