This review by Reis et al. explores the dichotomous role that the activation of the complement system in the tumor microenvironment has and how it can potentially be manipulated. Besides its role as an effector mechanism in antibody-mediated tumor cytolysis, the complement system can potentiate immunotherapy. An imbalanced complement activation can, on the other hand, serve a tumor-promoting role.
In tumour immunology, complement has traditionally been considered as an adjunctive component that enhances the cytolytic effects of antibody-based immunotherapies, such as rituximab. Remarkably, research in the past decade has uncovered novel molecular mechanisms linking imbalanced complement activation in the tumour microenvironment with inflammation and suppression of antitumour immune responses. These findings have prompted new interest in manipulating the complement system for cancer therapy. This Review summarizes our current understanding of complement-mediated effector functions in the tumour microenvironment, focusing on how complement activation can act as a negative or positive regulator of tumorigenesis. It also offers insight into clinical aspects, including the feasibility of using complement biomarkers for cancer diagnosis and the use of complement inhibitors during cancer treatment.