The ability of macrophages, a type of white blood cell, to transition into one of two forms, is critical for immune system functionality. These cells can morph into fighter cells (M1) that cause inflammation and attack invading pathogens, or nurse cells (M2) that soothe the inflammation and promote tissue repair after the battle. While researchers have known macrophages pivot to perform these functions, how this process occurs is not fully understood.
The University of Texas Health Science Center at San Antonio (UT Health San Antonio) scientists recently gained new insight into the macrophage polarization process, highlighting the importance of a certain protein’s (TRPM7) action on magnesium ion channels in the production of M2 cells. They also discovered a previously unidentified channel that is significant in M1 production.
In a study, published in January 2025 in Nature Partner Journals Precision Oncology, Brij B. Singh, PhD, associate dean for research, interim director of the Center for Regenerative Sciences and professor at the UT Health San Antonio School of Dentistry, reveals the essential role of magnesium in the transition of macrophages into M1 or M2 cells.
“In our lab, we are trying to understand how the cell knows which pathway to go, M1 versus M2, and how we can modulate that change if we want to,” Singh said.
In the future, TRPM7-focused cancer treatment could potentially be used proactively to prevent oral cancers in people who were prone to them or reduce cancerous tumors after they form.
What’s your sign? To fight or to fix
In a naïve state, macrophages get signals from other cell types, mostly cytokines. In a healthy person, if an infection or pathogen is detected, the cells make pro-inflammatory M1 types that heat up the pathogens and destroy them. Once the invasion is under control, the signal stops and cells trigger a reaction to halt M1 production and maintain naïve macrophages or switch to M2s.
When a person’s immune system is compromised, like when they have cancer, tumors can hijack certain pathways to trick the immune system into thinking they are normal cells and to not attack. By figuring out how the immune system is being deactivated by cancer, those pathways can be targets for treatment.
“That’s the beauty of how the immune system works and why most scientists are trying to tailor the system to use to our advantage. In the case of a high infection, you want M1 cells, which are important in killing tumors. Rather than having an innate immune response you want to target those specific cancer cells,” Singh said.
Magnesium channels moderate phenotype signaling
Previous research into calcium and other ion channels found downstream signaling pathways were important in both (M1 and M2) types of cells and how they switched forms. That study showed magnesium was also coming through the pathway. Up to that point, not much was known about the role of magnesium channels in macrophage plasticity.
Singh said initially they were merely interested in characterizing magnesium channels for these cell types, but the research team ended up with some key breakthroughs including the discovery that macrophages transitioning to M1s depend on a unique, previously undiscovered magnesium channel.
The scientists also found that M2 development was mediated by the TRPM7 protein’s action on the magnesium channel. While M2 cells are crucial in helping the body heal, due to their regenerative nature these cells also have the capacity to promote tumor growth. Targeting the TRPM7 channel could block M2 development and promote macrophage transition to the M1 phenotype.
To focus on how TRPM7 modulates the magnesium channel, they fed mice either magnesium-rich or magnesium-poor diets. The team then evaluated various magnesium channels to see which ones were essential in either M1 or M2 production. Mice fed magnesium-poor diets were more likely to produce M2 cells and have increased tumor growth.
“Magnesium binds to many proteins and is critical to proper functioning. M1 production needs a higher amount of magnesium,” Singh said.
Singh considered that magnesium is a much larger molecular compound than calcium or potassium, for instance, and may need a completely different transportation channel to bring in the entire amount.
TRPM7 action on magnesium channel moderates M2 development
When magnesium was depleted, TRPM7 was activated and macrophages turned into M2s. Mice supplied with adequate magnesium displayed a propensity to produce M1 cells.
The scientists used selective opioid receptor antagonist naltriben, a TRPM7 agonist, to block the action on the magnesium channel. This caused more macrophages to transition to M2 types. In mouse models of cancer, reversing this action caused tumors to shrink and, when given early enough, prevented tumor formation.
“In our studies we’ve seen that when you block magnesium, the macrophages transpose into a more M2-like polarization. They suppress the immune response, which means tumors can grow unchecked. The naltriben unintentionally fed tumor progression because it shapes the immune environment,” said co-investigator Viviane Nascimento Da Conceicao, PhD, a senior research scientist with the Department of Medicine, Division of Hematology and Oncology at UT Health San Antonio.
Nascimento Da Conceicao said the study provided a better understanding of the importance of magnesium transportation in immune system function.
“It was exciting to take a step forward in understanding how the tumor microenvironment shapes disease. Now that we know blocking the pathway helps tumors grow unchecked, we might be able to prevent tumors from shaping the immune environment that protects them from being attacked,” she said.
Singh’s lab is now investigating other TRPM7-targeting drugs with the assistance of a newly acquired Fluorometric Imaging Plate Reader (FLIPR) high-throughput screening system that can analyze hundreds of measurements per second.
“We can see which of these drugs is blocking intracellular mediation levels inside the cells through the TRPM7 and maybe screen all FDA-approved drugs and look for ones that are approved but have a similar structure to naltriben,” Singh said.
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Naltriben promotes tumor growth by activating the TRPM7-mediated development of the anti-inflammatory M2 phenotype
Viviane Nascimento Da Conceicao, Yuyang Sun, Manigandan Venkatesan, Jorge De La Chapa, Karthik Ramachandran, Rahul S. Jasrotia, Victor Drel, Xiufang Chai, Bibhuti B. Mishra, Muniswamy Madesh, Brij B. Singh
https://www.nature.com/articles/s41698-025-00815-x