Reducing sialylation in melanoma increases classical pathway-mediated complement activation

Strategies to reduce tumor sialylation have progressed to clinical trials, as they improved anti-tumor cellular responses in pre-clinical models. Immune responses against cancer are also mediated by soluble, non-cellular mechanisms, such as the complement system. Dysregulation of the complement cascade and hypersialylation are hallmarks of cancer. Sialic acids are known to interact with complement proteins. However, the downstream pathways involved in the regulation of the complement cascade when reducing sialylation in tumors remain unclear. Using melanoma cell lines and patient samples, we show that metabolic or enzymatic targeting of sialylation increases the activation of the complement, enhancing C3 deposition and membrane attack complex formation on tumor cells. This is mediated by the classical pathway of the complement, in line with increased binding of immunoglobulins to tumor cells when sialylation is impaired. Our work positions the complement cascade as a relevant anti-tumor response when sialylation is targeted for cancer treatment.