Complement in HER2-Positive Breast Cancer: A Conditionally Protective Mechanism Under Attack.
4 affiliations
- 1Clinic of Medical Oncology, Military Medical Academy, 1000 Sofia, Bulgaria.
- 2Department of Biology, Medical University of Varna, 9000 Varna, Bulgaria.
- 3Department of Biochemistry, Molecular Medicine and Nutrigenomics, Medical University of Varna, 9000 Varna, Bulgaria.
- 4Clinic of Pathology, Military Medical Academy, 1000 Sofia, Bulgaria.
Abstract
The therapeutic efficacy of anti-HER2 monoclonal antibodies in breast cancer has traditionally been attributed to direct inhibition of signaling and antibody-dependent cellular cytotoxicity (ADCC). Recent evidence, however, has established complement activation through the classical pathway as a possible adjunct mechanism underlying the synergistic activity of the trastuzumab and pertuzumab combination. This synergy is mediated by complement-dependent cytotoxicity (CDC) and complement-dependent cellular phagocytosis (CDCP), and is lost upon C1q deletion in preclinical models. Tumor cells evade complement-mediated killing through overexpression of membrane-bound complement regulatory proteins (mCRPs), particularly CD55 and CD59, which correlate with shorter disease-free survival in patients treated with trastuzumab. C1q itself plays a dual, context-dependent role: it acts as a complement-independent tumor suppressor in HER2-positive breast cancer while promoting tumor progression in most other malignancies. Emerging therapeutic strategies, including biparatopic antibodies such as zanidatamab, complement-redirecting immunoconjugates, and mCRP-targeting approaches, aim to overcome complement resistance and enhance antitumor immunity. On this basis, we propose that HER2-positive breast cancer represents a conditionally complement-protective tumor, in which the balance between antibody-directed complement activation and mCRP-mediated evasion determines treatment outcome. This review evaluates the current evidence linking complement to anti-HER2 therapy and highlights future directions for successful treatment.
Related
- Conditionally Significant eQTL and TWAS Analyses Identify MsRD26 as a Major Candidate Positive Regulator of Salt Tolerance in Medicago sativa L
- A lactate-HIF1-VDR positive feedback loop drives protective SPP1+ macrophage differentiation to inhibit schistosomiasis induced liver fibrosis
- Conditionally active antibody‒drug conjugates
- Co2ODE: Conditionally Coarse-Grained Model Discovery for Rewiring in Biochemical Networks
- Unraveling the use of vaccine therapy in HER2-positive breast cancer: a comprehensive review of current state and future perspectives
BibTeX
@article{petkova2026complement,
title = {{Complement in HER2-Positive Breast Cancer: A Conditionally Protective Mechanism Under Attack.}},
author = {Dobromira Petkova and Ivaila Kuleva and Zhasmin Stoyanova and Boryana Ilcheva and Albena Fakirova and Zhasmina Mihaylova and Maria Radanova},
journal = {Antibodies (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/antib15050091},
url = {https://europepmc.org/article/MED/42930033},
note = {CC BY},
}
RIS
TY - JOUR
TI - Complement in HER2-Positive Breast Cancer: A Conditionally Protective Mechanism Under Attack.
AU - Dobromira Petkova
AU - Ivaila Kuleva
AU - Zhasmin Stoyanova
AU - Boryana Ilcheva
AU - Albena Fakirova
AU - Zhasmina Mihaylova
AU - Maria Radanova
PY - 2026
DA - 2026/10/05
JO - Antibodies (Basel, Switzerland)
DO - 10.3390/antib15050091
UR - https://europepmc.org/article/MED/42930033
AB - The therapeutic efficacy of anti-HER2 monoclonal antibodies in breast cancer has traditionally been attributed to direct inhibition of signaling and antibody-dependent cellular cytotoxicity (ADCC). Recent evidence, however, has established complement activation through the classical pathway as a possible adjunct mechanism underlying the synergistic activity of the trastuzumab and pertuzumab combination. This synergy is mediated by complement-dependent cytotoxicity (CDC) and complement-dependent cellular phagocytosis (CDCP), and is lost upon C1q deletion in preclinical models. Tumor cells evade complement-mediated killing through overexpression of membrane-bound complement regulatory proteins (mCRPs), particularly CD55 and CD59, which correlate with shorter disease-free survival in patients treated with trastuzumab. C1q itself plays a dual, context-dependent role: it acts as a complement-independent tumor suppressor in HER2-positive breast cancer while promoting tumor progression in most other malignancies. Emerging therapeutic strategies, including biparatopic antibodies such as zanidatamab, complement-redirecting immunoconjugates, and mCRP-targeting approaches, aim to overcome complement resistance and enhance antitumor immunity. On this basis, we propose that HER2-positive breast cancer represents a conditionally complement-protective tumor, in which the balance between antibody-directed complement activation and mCRP-mediated evasion determines treatment outcome. This review evaluates the current evidence linking complement to anti-HER2 therapy and highlights future directions for successful treatment.
SN - 2073-4468
ER -