Nerve fibers within melanoma tumors may slow cancer growth

A new study from Weill Cornell Medicine suggests that nerve fibers within melanoma tumors may help slow cancer growth, adding a new dimension to how researchers understand tumor biology.

Published April 29 in Neuron, the study used mouse models to examine how peripheral nerves interact with melanoma tumors. Investigators, including David J. Simon, Ph.D., an assistant professor of biochemistry and biophysics at Weill Cornell Medicine, found that sympathetic nerve fibers, part of the body’s stress response system, can inhibit tumor growth by reducing tumor supportive macrophages, a type of immune cell.

“The nervous system typically has been considered as a driver of cancer growth, but here we’ve found that it can be a brake on cancer growth in some contexts,” Simon said in a news release. “Now the key will be to see how broadly relevant this is for human cancers, and how we can best step on that brake to help cancer patients.”

The findings challenge the long-standing view that nerves primarily promote cancer progression. Instead, they suggest the nervous system may play a dual role depending on the context.

Peripheral nerves form a communication network that connects the brain and spinal cord to the rest of the body. In the skin, sympathetic nerves release norepinephrine, a hormone involved in the fight or flight response that can also influence immune activity. Previous research has shown that nerves can suppress antitumor immunity and fuel tumor growth, but this study highlights a more complex interaction.

To better understand these dynamics, Simon and his team used whole mount immunolabeling, a technique that renders tissue transparent and allows for detailed mapping of nerve fibers. First author Tingting Liu, Ph.D., said the method enabled the team to trace how nerves infiltrate tumors and interact with surrounding cells.

The analysis showed that both sensory and sympathetic nerves increased as tumors grew, particularly in slower-growing melanomas. However, the two types of nerves appeared to have opposing effects. Sensory nerves promoted tumor growth, consistent with earlier findings, while sympathetic nerves slowed it.

Further investigation revealed that sympathetic nerves release norepinephrine, which activates alpha adrenergic receptors on nearby immune cells. These receptors were identified on tumor-associated macrophages, cells that tumors often manipulate to support their growth. Activation of these receptors reduced the number of macrophages in a tumor-supporting state, ultimately limiting tumor progression.

The findings may have implications for future cancer therapies. Targeting sympathetic nerve signaling or alpha adrenergic receptors could provide a new strategy for controlling tumor growth. Notably, drugs that act on these receptors are already widely used to treat high blood pressure, raising the possibility of repurposing existing treatments.

The research was supported in part by the Pershing Square Sohn Cancer Research Alliance, which enabled the team to explore nerve tumor interactions in greater detail.

Although the results are promising, researchers emphasized that further studies are needed to determine whether the same mechanisms apply in humans. Future work will focus on understanding how these nerve-related pathways function in clinical settings and whether they can be safely targeted in patients.