Abstract
The complement system plays a significant role in defending against pathogens and maintaining homeostasis in the host. Through complex, context-dependent mechanisms, the complement system interferes with nearly all hallmarks of cancer, either suppressing or promoting tumor growth. This review aims to analyze how the complement cascade and cell-intrinsic complement protein functions impact the metastatic process. We will discuss how complement contributes to local invasion and intravasation via epithelial-mesenchymal transition, affects tumor cell survival in circulation, extravasation, preparation of the pre-metastatic niche, colonization, and outgrowth at secondary sites. We present the rationale for targeting the complement cascade therapeutically, which is currently being tested in clinical trials with metastatic patients by either inhibiting or activating the cascade. As different therapeutic strategies enter clinical trials, we conclude with the importance of understanding the role of complement in each cancer type and subtype, as these roles may differ fundamentally, necessitating the validation of biomarkers to properly select patients for the appropriate clinical trials and combination therapies.