How Breast Tumors Hijack the Immune System to Grow Their Own Nerve Supply

Doctors have known for years that many solid tumors are threaded through with nerves, but exactly how those nerves get there has stayed murky. A new study from the University of Oklahoma, published in Cell Death & Differentiation, finally maps out the mechanism, at least for one especially aggressive cancer, and the answer involves an unexpected middleman: the tumor’s own immune cells.

Recruiting the Wrong Kind of Help

The team, led by Maureen Cox at the OU College of Medicine, focused on triple-negative breast cancer (TNBC), a form of the disease that lacks the three most common receptor targets used in other breast cancer treatments, which makes it notoriously hard to treat. They found that TNBC tumors recruit macrophages, the immune cells normally responsible for clearing infection and helping wounds heal, into the tumor microenvironment.

Once inside, those macrophages start behaving very differently than they would at, say, a cut on your skin. They release brain-derived neurotrophic factor (BDNF), a protein best known for helping neurons grow and form new connections inside the brain. In the tumor, BDNF acts as a chemical beacon, drawing nearby peripheral nerves inward, a process the researchers call axonogenesis. The nerves that grow into the tumor go on to support its growth and help it resist treatment.

“Macrophages are the critical source for drawing nerves into the tumor,” said Cox. “Although macrophages typically play a positive role in the body, they are facilitating a negative function in this scenario of breast cancer.”

Testing the Mechanism in Mice

To confirm macrophages were actually driving this process, rather than just being present alongside it, the researchers ran a set of causal experiments in mice. Tumors couldn’t grow when immune-derived BDNF was absent, and depleting macrophages from the tumor microenvironment compromised nerve infiltration. When the team then reintroduced normal macrophages into mice that otherwise lacked immune-derived BDNF, both tumor growth and nerve infiltration were restored, evidence that macrophages are both necessary and sufficient for this process.

The team then tested an intervention: a drug that blocks BDNF signaling. When nerves were prevented from infiltrating the tumor, tumor growth was significantly reduced. Notably, the drug used is already on the market for other conditions, which could shorten the path to clinical testing if the approach holds up in further research.

Does This Hold Up in People?

Mouse models are useful, but they don’t always predict what happens in human disease. So Cox’s team went back and analyzed data from actual triple-negative breast cancer patients. Tumors with higher levels of both macrophages and BDNF were associated with poorer survival outcomes, a pattern consistent with what the mouse experiments would predict, and a hint that the mechanism identified in the lab may be operating in real patients too.

Why Target the Nerves at All?

The strategic logic here is interesting: instead of attacking cancer cells directly, this approach targets the supporting cast around them. Cox’s working hypothesis is that the nerves growing into these tumors are immunosuppressive, meaning they may be actively dampening the body’s own anti-tumor immune response. If that’s true, stopping nerve infiltration in the first place could free up the immune system to do more of the work itself.

There’s still more to untangle. Some evidence suggests the nerves that infiltrate tumors also encourage new blood vessel growth, feeding the tumor oxygen and nutrients, while other research suggests tumor cells may use nerves as literal escape routes, crawling along them to spread to other parts of the body. Cox’s next steps include digging further into exactly how these nerves promote tumor growth, and testing the same BDNF-blocking approach in high-grade ovarian cancer, another notoriously difficult cancer to treat.

“Ultimately, we want to turn the anti-tumor immunity back on in cancer patients so their own immune systems can reject the tumors,” Cox said.

Original paper: Abbadi, J., Velayutham, R., Annan, A. C., et al. (2026). Macrophage-secreted brain-derived neurotrophic factor promotes tumor growth in triple-negative breast cancer by inducing axonogenesis. Cell Death & Differentiation. 

Source: How Breast Tumors Hijack the Immune System to Grow Their Own Nerve Supply