Constitutive activation of Notch signaling was found in melanoma cells. Using siRNA specifically knocking down Notch co-activator MAML1 blocked Notch down stream transcriptional repressor Hey1 expression, significantly upregulated TweakR and CCL2 mRNA and protein expression in melanoma cell line M624. Exogenous Tweak stimulated high level CCL2 production in siMAML transfected M624 cells, which was critically dependent on Tweak-TweakR ligation. CCL2 produced by siMAML1 transfected M624 stimulated with exogenous Tweak was functional chemoattractant to activated monocytes. This study supports targeting Notch signaling using small siRNA in melanoma cells may increase immune cell recruitment and restore natural immune surveillance in tumor microenvironment. (C) 2008 Elsevier Inc. All rights reserved.