Shedding light on the role of complement C4 activation in cancer

Complement C4 is a key component in the activation of classical and lectin complement pathways, which are observed in both animal tumor models and cancer patients. While its role in autoimmune disorders has been extensively studied, the functions of complement C4 and its activation in cancer have received inadequate consideration. Recent studies have detected C4 activation in animal tumor models and cancer patients, with its fragment C4d found in cancer tissues and lymph nodes. Elevated C4d levels could be a useful biomarker for detecting various cancers. This review aims to summarize recent developments on the role of complement C4 activation in promoting an immunosuppressive tumor microenvironment, thereby supporting tumor progression and metastasis; C4d as a biomarker; and its potential as a target for cancer immunotherapy. We also conduct a critical evaluation of methods used to measure complement C4 and its activation products, highlighting possible pitfalls and areas for improvement in existing research.