Here, we induced a prototypical CAC model by combined administration of azoxymethane (AOM) and dextran sulfate sodium (DSS) in the C57BL/6 genetic background mice with deficiency of C3, C5, C5ar1 or C5ar2, and revealed that C5aR1 signaling, independent of C3 activation, plays a key role in the colitis-associated colorectal tumorigenesis by modulating the cellular and molecular immune responses. The gene discussed is C3; the disease is colitis.