Ficolin-2 is an important serum complement lectin. Here, we describe novel findings indicating that serum ficolin-2 concentrations in multiple tumor patients are significantly lower than those in healthy donors. Administration of exogenous ficolin-2 or ficolin-A (a ficolin-2-like molecule in mouse), with only once, could remarkably inhibit the tumor cells growth in murine tumor models via early macrophages, dendritic cells (DCs) and CD8⁺ T cells, but not CD4⁺ T cells. Ficolin-A (FCN-A) knockout (KO) mice exhibits significantly increased tumor cell growth. Ficolin-2 induces macrophage activation, promotes M1 polarization and facilitates proliferation and antigen-specific cytotoxicity of CD8⁺ T cells. Ficolin-2 binds to Toll-like receptor 4 (TLR4) on macrophages and DCs and promotes their antigen-presenting abilities to CD8⁺ T cells. Our findings provide a new therapeutic strategy for tumors based on the triggering of immune-mediated antitumor effect by ficolin-2.