Stress-driven tumor-immune interactions in triple-negative breast cancer 4263

Abstract Description Breast cancer is the most diagnosed cancer among American women, with triple-negative breast cancer (TNBC) being particularly aggressive and disproportionately affecting young African American women. TNBC carries a threefold higher mortality risk than other subtypes. Chronic stress is a recognized risk factor for tumor progression, but its specific role in TNBC remains unclear. To explore this, 4T1-luciferase cells were implanted in the tibia or mammary pad of BALB/c and NSG mice, which were subjected to chronic stress through restraint for four weeks. Tumor microenvironment (TME) changes were analyzed via single-cell RNA sequencing (scRNA-seq) and flow cytometry. Chronic stress accelerated tumor progression and metastasis in both models. scRNA-seq and flow cytometry revealed that stress upregulated ADRβ2 in M2 macrophages and monocytes but downregulated it in CD8+ T cells. Selective ADRβ2 inhibition with Butaxamine significantly reduced tumor burden, decreased M2 macrophages and monocytes, and increased CD8+ T cells in BALB/c mice. Chronic stress also elevated TME nerve fiber density, and depleting peripheral nerves with 6-hydroxydopamine (6-OHDA) reduced tumor burden and decreased M2 macrophages and monocytes. These findings suggest chronic stress promotes TNBC progression via the tumor-neuroimmune network. Targeting ADRβ2 and nerve fibers may offer therapeutic potential for TNBC, especially in patients under chronic stress. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)