Deciphering the Intricate Roles of Radiation Therapy and Complement Activation in Cancer

The complement system consists of a collection of serum proteins that act as the main frontline effector arm of the innate immune system. Activation of complement can occur through 3 individual induction pathways: the classical, mannose-binding lectin, and alternative pathways. Activation results in opsonization, recruitment of effector cells through potent immune mediators known as anaphylatoxins, and cell lysis via the formation of the membrane attack complex. Stringent regulation of complement is required to protect against inappropriate activation of the complement cascade. Complement activation within the tumor microenvironment does not increase antitumoral action; instead, it enhances tumor growth and disease progression. Radiation therapy (RT) is a staple in the treatment of malignancies and controls tumor growth through direct DNA damage and the influx of immune cells, reshaping the makeup of the tumor microenvironment. The relationship between RT and complement activity in the tumor microenvironment is uncertain at best. The following review will focus on the complex interaction of complement activation and the immune-modulating effects of RT and the overall effect on tumor progression. The clinical implications of complement activation in cancer and the use of therapeutics and potential biomarkers will also be covered.