Methods and compositions are provided for treating melanoma in a mammalian subject by reducing, inhibiting or down-regulating tumor-associated macrophage (TAM) production or activity in the subject. The methods can involve a combination of reducing macrophage production and number while administering an anti-cancer therapy. The treatment can involve the combined blocking or down-regulating of the nucleic acid or protein expression or activity, or the downstream pathway of CCL-2 with the blocking or down-regulating of the nucleic acid or protein expression or activity, or the downstream pathway of a matrix metalloprotease (e.g., MMP9). Another aspect involves blocking the expression or activity of VEGF. Another aspect involves blocking or down-regulating the expression, activity or signaling of the MAPK pathway or the PI3K-AKT-mTOR pathway.
