Complement in HER2-Positive Breast Cancer: A Conditionally Protective Mechanism Under Attack

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.