When we think about cancer, we tend to focus on the tumor itself: the abnormal cells multiplying out of control. But a tumor doesn’t grow in isolation. It interacts with blood vessels, immune cells, surrounding tissue, and, researchers are increasingly discovering, even the body’s nervous system.
That last connection is particularly intriguing. Scientists have known for years that nerve fibers can grow into and around tumors, including breast tumors. What has been much less clear is why those nerves are there, how they get there, and whether the cancer somehow benefits from their presence.
New research from the University of Oklahoma is beginning to fill in those gaps. In an August 2026 study published in Cell Death & Differentiation, researchers investigated this process in triple-negative breast cancer, one of the more difficult forms of breast cancer to treat.
What they uncovered was an unexpected relationship between cancer, the immune system, and nerves. Rather than acting alone, the tumor appears capable of taking advantage of cells that would normally be part of the body’s defenses, setting off a chain of events that encourages nerves to grow into the tumor.
And those nerves may be doing much more than simply sitting there.
In experiments with mice, interfering with this process prevented nerves from infiltrating the tumors and significantly disrupted tumor growth. The researchers also found evidence in human triple-negative breast cancer samples suggesting that the same biological pathway may be relevant in people.
The findings are still early and don’t represent a new treatment for breast cancer. But they reveal a surprising way an aggressive cancer may manipulate its surroundings to help itself grow, while pointing researchers toward a potential vulnerability they hadn’t been targeting before.
What Makes Triple-Negative Breast Cancer So Difficult to Treat
Most breast cancers carry molecular “handles” that doctors can grab onto therapeutically. Triple-negative breast cancer is a type in which the tumor cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein on their surface. The absence of all three means the entire class of hormone-targeted drugs – drugs that have substantially improved survival for other breast cancer subtypes – simply don’t work.
Triple-negative breast cancer accounts for approximately 15 to 20 percent of all breast cancers, with a US incidence rate of 14.5 cases per 100,000 women based on 2021 data. The subtype is disproportionately represented among younger patients and, in particular, TNBC disproportionately affects non-Hispanic Black women, in whom about 21 percent of breast cancers are triple negative – roughly double the rate seen in other racial and ethnic groups.
TNBC tends to grow quickly, is more likely to have spread at the time it’s first found, and typically has fewer treatment options than most other types of breast cancer – a combination that produces survival rates generally lower than for other subtypes. Despite the approval of new TNBC targeted therapies in recent years, only a marginal increase in the five-year survival rate has been observed.
Standard treatment for triple-negative breast cancer includes surgery (lumpectomy or mastectomy), followed by radiation and chemotherapy. On the immunotherapy front, pembrolizumab – a drug that helps the immune system recognize and attack cancer cells – is approved for high-risk early TNBC and metastatic TNBC with PD-L1 expression. Atezolizumab was the first immunotherapy cleared for use in breast cancer, receiving FDA approval in March 2019 for metastatic TNBC with PD-L1 expression; pembrolizumab approvals in TNBC followed in 2020 and 2021. The treatment picture, while improving, remains limited, which has made the Oklahoma findings a focus of considerable attention in oncology.
How Tumors Build Their Own Nerve Supply
The Role of Axonogenesis in Breast Cancer Nerve Growth
Tumor-infiltrating nerves play critical roles in promoting tumor growth and progression. Upon transformation, tumors recruit surrounding peripheral nerves into the tumor microenvironment to obtain their own innervation, a process called axonogenesis. The existence of nerve networks within solid tumors has been known for years, but the cellular machinery responsible for initiating that recruitment remained unclear.
Neurotrophic factors like NGF and BDNF, which are highly expressed in the tumor microenvironment, can greatly stimulate axon growth and extension by interacting with their high-affinity receptors, TrkA and TrkB. These pathways are especially active in cancers such as pancreatic, prostate, and breast cancers. Prior to the Oklahoma study, lab dish experiments had suggested that tumor cells themselves might be the source of BDNF that triggers this nerve growth – but that assumption had never been tested in a living animal.
The Macrophage-BDNF Discovery
A team at the University of Oklahoma tested whether cancer cells themselves emit the BDNF signal and found that assumption wrong. The study in Cell Death & Differentiation, led by Jumana Abbadi with senior author Maureen Cox, Ph.D., an assistant professor in the Department of Microbiology and Immunology at the OU College of Medicine, reports that macrophages within triple-negative breast tumors secrete brain-derived neurotrophic factor, and that removing this single source prevents nerves from growing in and stops the tumor from growing at all.
Macrophages are not typically associated with nerve growth. Tumors influence macrophage differentiation and function, converting what should be a front-line immune defense into a cellular accomplice. “Macrophages are the critical source for drawing nerves into the tumor,” Cox said.
BDNF itself is well characterized in neuroscience. It is the most prevalent growth factor in the central nervous system and is essential for neuronal development and plasticity. Through activation of the TrkB receptor, BDNF promotes neuronal survival, synaptic plasticity, and neuronal growth. The Oklahoma proof, in a living model, established that immune cells inside a tumor – not the tumor cells themselves – are the primary BDNF source driving breast cancer nerve growth.
The Experimental Design
Abbadi and Cox’s team transplanted triple-negative breast cancer cells into intact mice and into mice engineered to lack immune-derived BDNF. In mice lacking immune-derived BDNF, the transplanted tumors could not grow. Depleting macrophages from the tumor microenvironment compromised innervation.
The confirming experiment ran in the other direction: transplanting normal bone-marrow-derived macrophages into the BDNF-deficient mice restored both innervation and tumor growth. This reciprocal design makes the causal claim considerably more robust than correlation-based studies. The new research suggests that tumor-associated macrophages can stimulate axonogenesis in a pathological setting, and 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.
What Nerves Do for a Growing Tumor
More Than Just Structural Scaffolding
The presence of nerve fibers inside a tumor isn’t biologically neutral. Nerves in tumors can regulate various biological processes, including angiogenesis (blood vessel formation), lymphangiogenesis (lymph vessel formation), immune function, inflammation, and extracellular matrix remodeling. Each of those processes can directly support a tumor’s survival and expansion.
A tumor needs a steady blood supply to keep growing beyond a certain size. Nerve-derived signals may activate signaling pathways that enhance the production of pro-angiogenic factors within the tumor – in effect, nerves help tumors summon the additional blood vessels they need to sustain rapid growth.
Nerves as a Metastatic Route
Beyond growth support, tumor innervation may carry a more alarming consequence. Research into perineural invasion – the process by which cancer cells travel along nerve fibers – has documented its role in metastasis. Interaction between the nervous system and breast cancer can influence tumor initiation, growth, invasion, metastasis, drug resistance, inflammation, and the immune system’s ability to combat cancer.
The Immune Suppression Connection
One of the more provocative implications of the Oklahoma study is what nerve infiltration may do to the tumor’s immune environment. “If we can stop the nerves from growing in the first place, maybe we can boost the immune response to help fight the cancer,” Cox said. Nerve-rich tumors may suppress the local immune attack that would otherwise damage cancer cells – creating a more protected microenvironment in which TNBC cells survive and divide with reduced opposition.
This connects directly to why immunotherapy is already a priority in TNBC. Breast cancer has traditionally been considered an immunologically “cold” tumor – one that is unresponsive to immunotherapy – but clinical trials in recent years have found immunotherapy to be effective for select patients. If nerve-mediated immune suppression is part of what makes TNBC resistant to treatment, then blocking nerve recruitment could, in theory, make these tumors more responsive to immune checkpoint inhibitors like pembrolizumab.
What the Human Data Show – and Where the Limits Are
Cox’s team also analyzed human triple-negative breast cancer samples, and found that tumors with higher levels of macrophages and BDNF were associated with poorer survival, suggesting the same pathway is active in people. The pattern in human tissue aligns with the mechanistic findings in mice, and strengthens the hypothesis that macrophage-driven breast cancer nerve growth is clinically meaningful – not just an artifact of the animal model.
Survival differences observed in patient tissue samples are correlational. Patients with higher macrophage and BDNF burdens may differ in many respects from those with lower levels, and observational human data cannot establish cause and effect. The mouse experiments provide the mechanistic evidence; the human data provide the clinical relevance signal. Together they form a compelling preliminary case – but not yet proof that blocking BDNF signaling will translate into longer survival in people with TNBC.
BDNF also has well-established roles in normal nervous system function throughout the body. Any therapeutic intervention that broadly suppresses BDNF signaling would need to demonstrate that the drug can disrupt tumor innervation without damaging healthy nerve tissue – a significant but not unprecedented pharmacological challenge.
The BDNF-Blocking Drug Experiment
In the mouse model, nerve density increased with tumor growth, and a drug targeting the relevant receptor decreased both nerve density and tumor growth. Cox and her team used a drug to block BDNF signaling in mice; nerves didn’t infiltrate the tumor, and tumor growth was significantly reduced. “It looks really promising that we can use this drug, which is already on the market, to target BDNF,” Cox noted.
The findings suggest that tumor-associated macrophages stimulate axonogenesis in a pathological setting – nerves are actively recruited rather than simply responding to signals already present. This creates a cellular feedback system in which cancer, immune cells, and nerves influence one another. Disrupting that loop at the BDNF step appears to collapse the entire system, at least in the mouse model.
Rather than targeting cancer cells directly, the findings point to a potential strategy in which future therapies block the communication between macrophages and the nerves that help tumors grow. That means acting on a supporting cell type – the macrophage – rather than on the cancer cell itself, a meaningful strategic departure from most current TNBC approaches.
Read More: Scientists Uncover the Hidden Nerve Network Fueling Breast Cancer
What Comes Next: Ovarian Cancer and Beyond
The University of Oklahoma team has identified a previously underappreciated mechanism by which triple-negative breast cancer may turn the immune system and peripheral nervous system into allies – and they aren’t stopping at breast cancer. Cox now plans to investigate whether the same macrophage-BDNF-nerve axis is active in high-grade ovarian cancer, which shares several aggressive characteristics with TNBC and similarly lacks effective targeted treatments. “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.
In the past two years, significant progress has been made in understanding axonogenesis and developing research models that enhance insight into nerve-tumor interactions within the tumor microenvironment. Recent studies have identified key signaling pathways and molecular mechanisms crucial for tumor-induced axonogenesis. The Oklahoma work adds to this growing body of evidence the immune cell responsible for initiating nerve recruitment in a living tumor model – a piece that was missing from the mechanistic picture.
What This Means for Patients Now
For patients with TNBC today, the current standard of care remains surgery, chemotherapy, radiation, and pembrolizumab for eligible high-risk cases. The macrophage-BDNF pathway is not yet a treatable target. Getting from a mouse study to a human clinical trial takes years and requires showing both safety and efficacy in people – but the Oklahoma team has a concrete starting point: drug candidates that modulate BDNF signaling already exist in neuroscience research pipelines, and tumor innervation is a measurable endpoint that could serve as a biomarker in early-phase trials.
Three findings from the 2026 study carry direct implications for how researchers think about breast cancer nerve growth. Macrophages – not tumor cells – are the primary BDNF source driving nerve infiltration into triple-negative breast tumors, confirmed through a rigorous reciprocal mouse model. Blocking BDNF signaling with a drug already on the market prevented nerve infiltration and significantly reduced tumor growth in those mice. And in human TNBC tissue, higher macrophage and BDNF levels correlated with worse survival outcomes, bridging the animal model to clinical relevance. A study in human cancer tissue that tests whether disrupting this pathway changes the tumor immune environment – in the ways the mouse data predict – is the logical next step, and the Oklahoma group is positioned to run it.
Disclaimer: This information is not intended to be a substitute for professional medical advice, diagnosis, or treatment and is for information only. Always seek the advice of your physician or another qualified health provider with any questions about your medical condition and/or current medication. Do not disregard professional medical advice or delay seeking advice or treatment because of something you have read here.
AI Disclaimer: This article was created with the assistance of AI tools and reviewed by a human editor.
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