Naltriben promotes tumor growth by activating the TRPM7-mediated development of the anti-inflammatory M2 phenotype.

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