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Complement is a cascade of blood proteins that punches holes in things marked by antibodies and calls in inflammatory cells. Therapeutic antibodies such as rituximab use it to kill cancer cells; tumours defend themselves with shields (CD46, CD55, CD59), and the cascade's own by-products (C5a) can recruit the myeloid cells that protect the tumour.
Three routes converge on C3 convertase: classical (C1q binding IgG1/IgG3 Fc clusters, the basis of complement-dependent cytotoxicity by rituximab, obinutuzumab less so, daratumumab), lectin, and alternative (spontaneous C3 tick-over). C3b opsonises for phagocytosis via CR3; C5 convertase releases C5a and assembles the membrane attack complex (C5b-9). Tumours over-express membrane regulators CD46, CD55 (DAF) and CD59 (protectin) and secrete factor H, limiting CDC; CD20 shaving and antigen loss add to rituximab resistance. Conversely, intratumoural complement activation is often pro-tumour: C5a-C5aR1 and C3a-C3aR recruit and activate MDSCs and neutrophils, suppress CD8 T cells, and promote angiogenesis; C1q from macrophages supports invasion. Blocking C5aR1 (avdoralimab) with anti-PD-1 was tested; complement is also a mediator of infusion reactions and of CAR-T-associated inflammation. Fc engineering (afucosylation for ADCC versus hexamerisation for CDC) tunes which effector dominates.
A demolition crew that follows the flags an antibody plants on a building: they blow holes in the walls (membrane attack complex) and call in the bulldozers (phagocytes). Tumours paint over the flags (CD55, CD59), and the noise of the demolition attracts the wrong kind of crowd (C5a-recruited suppressor cells).
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