The tumor microenvironment is a complex tissue composed of various stromal cells including immune cells. Especially, tumor-associated macrophages (TAM) are one of the major components of tumor tissues, and they play a pivotal role in prompting the various tumor growths by producing growth factors and reactive oxygen species (ROS). Previously, we have reported that TRPM2 channel, a ROS-sensitive Ca²⁺ channel, is abundantly expressed in macrophages and is tuning gene expression via transcription factor NF-kB. Here, we report the significance of TRPM2 channel in the regulation of pro-inflammatory M1 and pro-angiogenic M2 phenotype of TAM. In TRPM2 knockout mice, TAMs around s.c.-injected B16F10 melanoma tumor showed strong expression of M2 phenotypic markers and proangiogenic factor VEGF according to the enhanced activity of Stat3. Interestingly, blood vessels in TRPM2 knockout mice tumor were so-called non-productive, which is characterized by an increase in vascular density and decrease in tissue perfusion and thus the tumor progression was suppressed. We also found that the activation of TRPM2 channel induced by H₂O₂ suppress the activity of Stat3 in vitro. Importantly, TRPM2 protein showed physical interaction with Stat3 protein, and their complex was degraded gradually in the presence of H₂O₂. Therefore, our data suggest that TRPM2-Stat3 complex is critical for handling the phenotypes of macrophages depending on the environmental oxygen/redox conditions.