The aberrant activation of multiple interconnected signaling pathways poses a big challenge to scientists trying to pinpoint the specific mechanisms of melanoma progress and development need to overcome. On the other hand, as an exponent of reconfigured signaling pathways, melanoma is an attractive option for targeted drug development [1] and microenvironment-targeted therapies. The ability of co-administered simvastatin and DMXAA (5, 6-dimethylxanthenone- 4-acetic acid) to suppress the aggressive phenotype of B16.F10 melanoma cells co-cultured with tumor associated macrophages under hypoxia-mimicking conditions was already demonstrated by our in vitro studies [2]. Therefore, our next aim was to encapsulate the two therapeutic agents in efficient delivery systems represented by long circulating liposomes and to test them on a more complex in vivo murine melanoma model. Consistent with our previous findings, the combined liposomal drug therapy inhibited the expression/production levels of several key molecules involved in promoting the invasive capacity of tumor cells (HIF-1α, pAP1-cJun, MMP-2, MMP-9, IL-1β). The immunohistochemical examination of tumor tissues revealed a decrease in tumor angiogenesis and an increase in macrophage infiltration. Decreased expression of ARG-1 and iNOS in the context of an abundant macrophage infiltration suggests an immunomodulatory effect of the liposomal combined therapy which might overcome drug resistance. In conclusion, this novel targeted therapy holds the potential to shift the balance towards an anti-tumorigenic melanoma microenvironment. [ABSTRACT FROM AUTHOR]