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In cancer, the extracellular matrix is extensively remodeled during chronic inflammation, thus affecting cell transcription, differentiation, migration and cell-cell interactions. Matrix metalloproteinases can degrade the extracellular matrix of tumor tissues and take important roles in disease progression. Numerous efforts to develop cancer treatments targeting matrix metalloproteinases have failed in clinical trials owing to the ineffectiveness and toxicity of the applied inhibitors. In this study, we investigated the potential of targeting matrix metalloproteinases and oncolytic virus combination in cancer therapy. We found that MMP3 expression was upregulated in various cancers and MMP3 expression in the tumor cells, but not in other tissues, was important for tumor growth and metastasis. Single treatment of colon cancer with multiple MMP3 inhibitors was not effective in mice. Nevertheless, the therapeutic effect of MMP3 was greatly improved by combination with an oncolytic virus. A potential mechanism of MMP3 in regulating tumor cell proliferation and invasion was mediated via Erk1/2 an NF-κB signaling. This study reveals that MMP3 is a promising target and the combined treatment with oncolytic virus is a potential strategy for cancer therapy.