Background: Cancer immunotherapy based on direct intratumoral injection of immunomodulators has been established at the end of 19th century using Coley's toxin. Our novel therapeutic strategy is based on the intratumoral injection of optimized mixture of TLR agonists, causing strong inflammatory infiltration. Infiltrating cells (mainly phagocytes) are directed to artificially opsonized tumor cells covered by phagocytosis stimulating ligands. Materials and methods: Immunotherapy was tested using B16-F10 murine melanoma model. Inflammatory infiltration was achieved using the mixture of resiquimod, poly(I:C), and lipoteichoic acid. Artificial opsonisation of tumor cells was elicited by mannan anchored to cell membranes using a hydrophobic anchor. The course of tumor infiltration was studied using flow cytometry. Cytotoxic effect of infiltrating immune cells on opsonized tumor cells was studied in vitro. Participation of acquired immunity was elucidated on the basis of intracellular IFN-gamma production by lymphocytes. Results: Optimized cancer immunotherapy based on the synergy of TLR agonists with artificially induced tumor opsonisation resulted in complete cure of 83% of mice with advanced melanomas. Moreover, cured mice acquired resistance to retransplantation of tumor cells. Applied therapy has a strong antimetastatic effect. In the first phase of immunotherapy, granulocyte predominance was observed, followed by involvement of acquired immunity. Conclusions: Intratumoral immunotherapy initiated by innate immunity based attack followed by joining of mechanisms of acquired immunity is a promising approach for future application in clinical practice as compounds used are safe for humans.