Abstract: The present invention relates to a method and composition for treating melanoma, aggressive/invasive melanoma, metastatic melanoma or melanoma resistant. More particularly, inventors have shown that high expression of PTX3 correlates with melanoma invasiveness and with a poorer survival rate in metastatic melanoma patients. PTX3 knockdown inhibited melanoma cell migration, invasion, lung metastasis, and NF?B signaling pathway. An addition of melanoma-derived or recombinant PTX3, or overexpression of PTX3 enhanced motility of low migratory cells. Finally, they found that TLR4 and MYD88 knockdown or targeting inhibited PTX3-induced melanoma cell migration, suggesting that PTX3 functions through a TLR4/NF?B-dependent pathway.