What if a cancer treatment could attack a tumor by disrupting its energy supply—and work more strongly when paired with an existing drug? In mice, that is what this study found, while the same substance also limited weight gain on a high-fat diet.

Cancer cells use energy differently from normal cells. That difference suggests that changing energy use could create conditions unfavorable for cancer growth without greatly harming normal tissues. Energy changes also affect immune cells, while substances released by cancer cells can change the tumor surroundings and the immune cells inside them.

So the connection between tumor energy use and immunity has become an important part of cancer treatment research, because carefully changing metabolism might strengthen the body’s anticancer response. The study examined how continuous M4N consumption affected energy metabolism in healthy mice, using changes in body weight as an indicator.

It also studied the effects of giving M4N together with temozolomide every day on energy metabolism in glioblastoma tumors implanted in mice. The idea was to strengthen M4N by adding a second cancer drug. Earlier work had found stronger combined effects in many human cancer cells and in tumors implanted in mice.

In brain, pancreatic, and liver tumors, combinations with temozolomide or sorafenib increased the survival of mice with cancer, while the individual drugs did not significantly improve survival. But the same kind of combined killing was not seen in slow-growing mouse heart cells, unlike in many cancer cells.

The researchers then tried the idea in healthy mice eating high-fat food. Mice whose food contained M4N gained less weight than mice eating the same kind of food without it. That difference was not explained by eating less: both groups consumed almost the same amount of food.

M4N was found in several organs, with the highest amounts in the digestive tract and high amounts in fatty tissue. The combination treatment reduced lactate and malate, while related findings showed suppression of glycolysis, an important route for making energy.

One key energy-making enzyme was reduced somewhat by temozolomide and much more by the combination. The data indicate that the combination suppressed one energy route by reducing this enzyme. The treatment also reduced oxygen use by glioblastoma cells, indicating that it suppressed another way cells generate energy inside their mitochondria.

Across brain, pancreatic, and liver tumors, pairing M4N with another cancer drug sharply improved tumor control or survival, but the same combinations did not make heart cells die more than expected—suggesting a potentially useful cancer-selective effect. The combination treatment disrupts cancer cells’ fuel production at several points: it reduces sugar breakdown, weakens the cell’s energy-making machinery, and lowers the supply of NAD-plus and FAD needed to keep metabolism running.

This matters because the treatment makes cancer cells less able to survive while rapidly removing HIF1A, a protein that helps cells cope with low oxygen. The messenger RNA stays essentially unchanged, pointing to destruction of the existing protein rather than reduced production.

Together, the treatments pushed tumor cells into a strong stress response and increased harmful oxygen activity in cultured cells. That matters because it links disrupted energy use to damage that may help explain the combination’s anticancer effect. In mice with implanted glioblastoma tumors, M4N changed lactate, 2-hydroxyglutarate, and itaconate—substances that can influence immunity and inflammation around a tumor.

The combination treatment reduced lactate and also reduced 2-hydroxyglutarate in the tumors. M4N suppresses energy metabolism in glycolysis and the TCA cycle by modulating proteins; the resulting reduction in energy metabolism activates ER stress mechanisms.

That stress, along with weakened energy-transfer systems, increases reactive oxygen species, especially when M4N is paired with another cancer drug. Very high levels can produce anticancer effects. The combination also lowers substances that suppress immune-cell function and increases itaconate production in macrophages inside tumors, so the surrounding immune environment may become more hostile to cancer.

The findings suggest that combining M4N with selected anticancer drugs could be an effective approach toward possible complete remission of human cancer. Its effects may involve both energy metabolism and immune-related metabolism, because the combination reduced oncometabolites such as lactate or two-HG.

Because efficient energy metabolism is crucial for the survival of cancer cells, M4N combination treatment could potentially apply to cancers of heterogeneous origin. The study suggests that combining M4N with temozolomide can weaken a brain tumor’s energy production and reshape its surrounding environment, making combination treatment a possible path worth testing beyond this mouse study.