UNC93B1介导乳腺癌中IL-6/STAT3依赖的肿瘤与巨噬细胞之间的信号交互，并促进上皮-间质转化过程。

Abstract

Background Lipid metabolic reprogramming is increasingly recognized as a driver of breast cancer progression; however, how lipid metabolism-associated risk states are translated into immune remodeling and epithelial–mesenchymal transition (EMT) remains unclear. This study aimed to identify a lipid metabolism-related regulator that mediates tumor–macrophage crosstalk and to experimentally define its role in breast cancer progression. Methods Lipid metabolism-related immune regulatory candidates were identified through integrated bulk transcriptomic, machine-learning, single-cell, and spatial transcriptomic analyses. UNC93B1 was prioritized for experimental validation using immunohistochemistry, gain- and loss-of-function assays, tumor cell–macrophage co-culture, ELISA, IL-6 neutralization, and STAT3 inhibition/rescue experiments. Results Integrated multi-omics analysis prioritized UNC93B1 as a lipid metabolism-associated immune regulatory hub in breast cancer. UNC93B1 was associated with high lipid metabolism risk status, invasive tumor phenotypes, and stronger expression in aggressive molecular contexts, particularly HER2-enriched and triple-negative breast cancer samples. Single-cell and spatial transcriptomic analyses further linked UNC93B1 to myeloid/macrophage-enriched states, M2-like macrophage polarization, and Toll-like receptor-related immune niches. Experimentally, UNC93B1 knockdown suppressed breast cancer cell proliferation, migration, invasion, STAT3 activation, and EMT, whereas UNC93B1 overexpression produced the opposite effects. In tumor cell–macrophage co-culture systems, tumor cell-derived UNC93B1 enhanced IL-6 secretion, activated STAT3 signaling in macrophages, and promoted M2-like polarization. Reciprocally, macrophage-associated IL-6/STAT3 signaling reinforced EMT and invasive behavior in breast cancer cells. IL-6 neutralization and STAT3 inhibition markedly disrupted this paracrine feedback loop, confirming that UNC93B1 promotes breast canc