Abstract 1208: The neuroimmune impact of chronic stress on triple-negative breast cancer

Breast cancer is the most frequently diagnosed cancer among American women, with triple-negative breast cancer (TNBC) being particularly aggressive and disproportionately impacting young African American women. TNBC has a threefold higher mortality risk compared to other breast cancer subtypes. Although chronic stress has been recognized as a risk factor that promotes tumor progression, its specific impact on TNBC progression and metastasis remains unclear. To investigate the role of chronic stress in TNBC, 4T1 cells were implanted in the tibia or fourth mammary pad of BALB/c and NSG mice. Mice were subjected to chronic stress through restraint over four weeks. The tumor microenvironment (TME) change was analyzed using single-cell RNA sequencing (scRNA-seq) and flow cytometry. Chronic stress accelerated tumor progression and metastasis in both BALB/c and NSG mouse models of TNBC. scRNA-seq and flow cytometry analysis revealed that chronic stress significantly upregulated ADRβ2 expression in M2 macrophages and monocytes but downregulated it in CD8+ T cells relative to controls. Notably, selective inhibition of ADRβ2 with Butaxamine significantly decreased the tumor burden, reduced M2 macrophage and monocyte numbers, and increased TCD8+ cells in the TME of BALB/c mice compared to the control group. Moreover, chronic stress elevated nerve fiber density within the TME of BALB/c and NSG mice. Depletion of peripheral nerve fibers using 6-hydroxydopamine (6-OHDA) significantly reduced tumor burden and correspondingly decreased M2 macrophages and monocytes in the TME compared to the control group. These findings suggest that chronic stress promotes TNBC progression and metastasis by modulating the tumor-neuroimmune network within the TME. Targeting components of this network, such as ADRβ2 and nerve fibers, may offer new therapeutic avenues for managing TNBC, especially in patients under chronic stress. Citation Format: Chao Zhang, Lizhong Wang, Runhua Liu. The neuroimmune impact of chronic stress on triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1208.