Triple-Negative Breast Cancer “Recruits” Nerves via Immune Cells, Mouse Study Pinpoints BDNF Signaling

Triple-negative breast cancer lacks the common hormone and HER2 treatment targets, prompting researchers to increasingly focus on the “accomplices” surrounding tumors. A mouse study suggests that breast cancer not only exploits immune cells but may also use them to draw sensory nerves into tumors, creating a microenvironment conducive to growth.

At the core of this pathway are tumor-associated macrophages. Macrophages normally help clear pathogens and repair wounds, but the research team found that in mice implanted with Py230 triple-negative breast cancer cells, these cells were the main immune-cell source of brain-derived neurotrophic factor, or BDNF, within tumors. BDNF can prompt existing nerves to extend new axons, allowing tumors to gradually establish their own innervation.

When the researchers removed immune-cell-derived BDNF, 60% of the mice failed to develop tumors; tumors that did form were also smaller and had less sensory nerve distribution. Depleting tumor-associated macrophages similarly reduced nerve ingrowth. Conversely, after macrophages capable of normally secreting BDNF were transferred into mice lacking immune-cell-derived BDNF, tumor growth resumed in 78% of the animals, and innervation was reestablished. These findings support that, in this model, macrophages are both necessary and sufficient as a key source of BDNF.

The research team also verified this association from the neural side: after specific sensory nerves were eliminated through pharmacological or genetic methods, tumor growth was suppressed across multiple mouse models of triple-negative breast cancer. Further use of the broad-spectrum TRK inhibitor entrectinib to block neurotrophic factor signaling reduced tumor volume and nerve distribution in two mouse models, indicating that the “macrophage–BDNF–sensory nerve” pathway may form a biological axis that could be targeted.

Human data currently provide only indirect clues. After analyzing breast cancer data from The Cancer Genome Atlas, the researchers found that concurrently high macrophage infiltration and BDNF expression were associated with poorer survival outcomes. However, such data can only indicate an association and cannot prove that BDNF-mediated nerve recruitment causes disease progression, nor can they replace validation in human tumor tissue and clinical trials.

The findings remain preclinical and are derived primarily from mice with transplanted tumors. Some experiments had limited sample sizes, and entrectinib was not specifically designed for this pathway. In addition to confirming whether tumors from different patients depend on the same mechanism, the next steps must clarify how to selectively block signaling within tumors without disrupting the important functions of BDNF and sensory nerves in normal tissues.