OKLAHOMA CITY—A study from the University of Oklahoma has identified a previously underappreciated mechanism by which triple-negative breast cancer may turn the immune system and peripheral nervous system into allies. Researchers report that macrophages—immune cells best known for engulfing pathogens, clearing damaged tissue and supporting wound repair—can release a nerve-growth protein that draws axons into tumors. Once established, these nerve fibers appear to help the cancer grow and resist treatment.
The findings, published in Cell Death & Differentiation, offer a mechanistic explanation for a biological feature that has puzzled cancer researchers for years. Many solid tumors contain dense networks of nerves, a phenomenon known as tumor innervation, but the signals that guide nerves into malignant tissue have remained incompletely understood. In triple-negative breast cancer, the researchers found that macrophages serve as an essential intermediary between the tumor and the nervous system.
Triple-negative breast cancer lacks three molecular targets commonly used to classify and treat breast tumors: the estrogen receptor, the progesterone receptor and the HER2 protein. Because these tumors do not respond to therapies directed against those receptors, treatment typically relies on chemotherapy, immunotherapy and, in selected cases, other targeted approaches. The disease can be aggressive, and the discovery of a pathway linking immune cells, nerves and tumor progression could open a new direction for therapeutic development.
The central signal identified by the team is brain-derived neurotrophic factor, or BDNF. This protein is widely recognized for its role in the nervous system, where it supports neuronal survival, differentiation and the growth of axons—the long projections that transmit signals between nerve cells. In the tumor microenvironment, however, BDNF appears to be repurposed as a chemical guidance signal. Macrophages that accumulate within triple-negative breast tumors secrete BDNF, creating conditions that encourage nearby nerve fibers to extend toward and infiltrate the malignant tissue.
Axonogenesis, the formation and extension of axons, is normally a tightly regulated process involved in the development and repair of the nervous system. The new research suggests that tumor-associated macrophages can stimulate this process in a pathological setting. Rather than simply responding to nerve signals already present in the tissue, the nerves may be actively recruited by immune cells that have been drawn into the tumor. This creates a cellular feedback system in which cancer, immune cells and nerves influence one another.
“Macrophages are the critical source for drawing nerves into the tumor,” said Maureen Cox, Ph.D., an assistant professor in the Department of Microbiology and Immunology at the OU College of Medicine and a research member of OU Health Stephenson Cancer Center. Although macrophages commonly contribute to host defense and tissue repair, their behavior can change inside tumors. Tumor-associated macrophages frequently adopt functions that suppress effective anti-cancer immunity, remodel surrounding tissue and support the formation of blood vessels.
Cox and her colleagues tested whether interrupting the BDNF pathway could prevent tumor innervation. In mouse models of triple-negative breast cancer, pharmacological inhibition of BDNF signaling reduced the infiltration of nerves into tumors and significantly slowed tumor growth. The result suggests that BDNF is not merely a marker of tumor-associated nerve growth but may be a functional component of the process. Because the inhibitor used in the experiments is already available clinically for another purpose, the researchers say the pathway could be investigated further as a potential drug-repurposing strategy, although its safety and effectiveness in breast cancer patients remain unproven.
The biological consequences of tumor innervation are still being mapped. One possibility is that nerves promote the development of blood vessels, supplying tumors with oxygen and nutrients that support expansion. Nerve-derived signals may also alter the behavior of cancer cells, stromal cells and immune populations within the tumor microenvironment. In addition, previous research has suggested that malignant cells can migrate along nerve structures, potentially enabling them to escape the primary tumor and invade distant tissues. The Oklahoma team is now working to determine which of these mechanisms are most important in triple-negative breast cancer.
The researchers also examined patient data to assess whether the mouse findings corresponded to patterns in human disease. Tumors containing higher levels of macrophages and BDNF were associated with poorer survival among patients with triple-negative breast cancer. This correlation does not establish that macrophage-derived BDNF directly causes a worse outcome, but it supports the possibility that the pathway observed in experimental models also operates in human tumors. The results further suggest that macrophage abundance and BDNF activity could eventually help identify tumors with particularly active nerve–immune interactions.
Cox’s group plans to investigate how the newly recruited nerves suppress anti-tumor immunity and whether blocking their development can improve responses to existing treatments. The researchers also intend to test the approach in high-grade ovarian cancer, another difficult-to-treat malignancy that may share features of an immune-suppressed, nerve-rich tumor microenvironment. If future studies confirm that macrophages initiate tumor innervation and that the resulting nerves shield cancer from immune attack, therapies aimed at BDNF signaling could complement treatments designed to activate the immune system. The long-term goal, Cox said, is to restore anti-tumor immunity so that patients’ own immune defenses can more effectively reject malignant cells.
Subject of Research: Animals
Article Title: Macrophage-secreted brain-derived neurotrophic factor promotes tumor growth in triple-negative breast cancer by inducing axonogenesis
News Publication Date: 2-Jul-2026
Web References: https://www.nature.com/articles/s41418-026-01796-5
References: Cell Death & Differentiation, DOI: 10.1038/s41418-026-01796-5
Keywords: Triple-negative breast cancer, macrophages, brain-derived neurotrophic factor, BDNF, axonogenesis, tumor innervation, nerve fibers, tumor microenvironment, cancer immunity, tumor growth
Tags: biological mechanisms of tumor innervationcancer tumor innervationchallenges in treating triple-negative breast cancerimmune system and peripheral nervous system in cancermacrophage-mediated nerve recruitment in breast cancermechanisms of nerve-guided tumor growthnerve-growth proteins in tumor microenvironmentrole of macrophages in cancer progressiontriple-negative breast cancer growth mechanismstumor microenvironment and nerve interactionstumor resistance to therapy due to nerve infiltrationtumor-associated nerve fibers
