The tumor microenvironment is heavily influenced by macrophages, which can shift between an anti-tumor M1 phenotype and a pro-tumor M2 phenotype. This plasticity is often exploited by tumors to evade immune responses. Our study investigates how Naltriben, a pharmacological compound, contributes to tumor progression by activating TRPM7, a mechanosensitive ion channel involved in Mg²⁺ homeostasis and cellular signaling. We found that TRPM7 activation skews macrophages toward an M2-like phenotype, ultimately promoting tumor growth.

TRPM7 is a dual-function protein with both ion channel and kinase activity, playing a critical role in Mg²⁺ transport. Since Mg²⁺ is essential for macrophage function, we explored whether Naltriben-induced TRPM7 activation affects macrophage polarization. RNA sequencing and protein analysis revealed that Naltriben increases TRPM7 activity, leading to an upregulation of M2 markers (CD206, Arg1, IL-10) and a decrease in M1 markers. Further, Mg²⁺ supplementation enhanced the M2 shift, suggesting that the immunosuppressive effects of Naltriben are mediated by TRPM7's regulation of Mg²⁺ homeostasis.

To confirm TRPM7's role, we used TRPM7 inhibitors and siRNA knockdown. Blocking TRPM7 restored M1-like characteristics in macrophages, reducing IL-10 secretion and increasing pro-inflammatory cytokine expression. This suggests that Naltriben’s tumor-promoting effects are not direct but rather occur through Mg²⁺-dependent TRPM7 activation, which drives an immunosuppressive macrophage state.

To validate these findings, we examined in vivo tumor models. Mice injected with Naltriben-treated macrophages developed significantly larger tumors than controls. Immunohistochemistry confirmed an increase in M2 macrophages within the tumor microenvironment, supporting the idea that TRPM7 activation contributes to immune evasion. Interestingly, tumors in TRPM7-inhibited mice showed reduced growth, reinforcing its role as a key regulator of macrophage function.

Our study identifies TRPM7 as a critical link between Mg²⁺ homeostasis and macrophage polarization, with significant implications for cancer immunology. It also raises concerns about the off-target effects of pharmacological compounds like Naltriben, which may inadvertently promote tumor growth by altering Mg²⁺-dependent immune responses. Future work will focus on developing TRPM7-targeted therapies to prevent macrophage-driven tumor progression and further explore the role of Mg²⁺ in immune regulation.