<p>Macrophage plasticity is critical for maintaining immune function and developing solid tumors; however, the macrophage polarization mechanism remains incompletely understood. Our findings reveal that Mg²⁺ entry through distinct plasma membrane channels is critical to macrophage plasticity. Naïve macrophages displayed a previously unidentified Mg²⁺ dependent current, and TRPM7-like activity, which modulates its survival. Significantly, in M1 macrophages, Mg²⁺ entry is facilitated by a novel Mg²-dependent current that relies on extracellular Mg²⁺, which was crucial for activating iNOS/NFκB pathways and cellular bioenergetics, which drives pro-inflammatory cytokines. Conversely, in M2 macrophages, Mg²⁺ entry occurs primarily through TRPM7 channels, pivotal for IL-4 and IL-10-mediated anti-inflammatory cytokine secretion. Notably, the Mg²⁺ deficient diet or addition of TRPM7 agonist Naltriben suppresses the M1 phenotype while promoting angiogenic factors and fostering tumor growth. These findings suggest that Mg²⁺ flux via specific channels is indispensable for macrophage polarization, with its dysregulation playing a pivotal role in tumor progression.</p>