INTRODUCTION AND OBJECTIVES: In tumor microenvironments, immune cells population is heterogeneous with different functions in tumor development. Tumor-associated macrophages (TAMs) can acquire tumor-promoting characteristics exhibiting an M2-like profile. Our group demonstrated that lipoxin (LX), an important pro-resolving lipid mediator, trigger antitumor effects by TAM through specific and selective M2-profile inhibition since LX does not alter M2 phenotypes. These evidences suggest that LX modulates these effects by signaling pathways not yet studied. Thus, our objective is to investigate the cellular and molecular mechanisms involved in the LX effects on the differential polarization of macrophages (Mphi). MATERIAL AND METHODS: To obtain TAMs, Mphi derived from human monocytes were incubated with conditioned medium of MV3, a human melanoma cell lineage. RESULTS AND CONCLUSION: By western blotting assay, we have seen that LX decreases the activation of the ERK pathway in TAMs and M2, while have no effect in M1 macrophages. In the other hand, we observed that LX enhances AKT phosphorylation in TAMs, suggesting that LX modulate PI3K/Akt/mTOR that could lead to M1-like polarization. Furthermore, LX potentiate the activation of STAT-3 already increased in TAM. In this study, we observed that LX effects depends on previous VEGFR activation by tumor-secreted VEGF. In addition, LX does not alters VEGF levels secreated by TAMs. Furthermore, lipoxin decreases VEGFR-1 phosphorylation and increases the expression of SHP-1, a tyrosine phophatase, suggesting that the effect of lipoxin on VEGF modulation in TAMs may due to down-regulation of VEGFR by SHP-1. Our results suggest that lipoxin modulates the polarization of TAMs modulating important macrophage-activated signaling pathways in the tumor microenvironment, such as the action of growth factors and activation of gene transcription factors.