Introduction Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options. Reprogramming the tumor immune microenvironment (TIME) has emerged as a promising strategy for breast cancer treatment, and tumor-associated macrophages, the most abundant and heterogeneous immune cells in the solid TIME, play a pivotal role in this process. This study aimed to investigate the TNBC-specific TIME. Methods Multiplex fluorescence immunohistochemistry and bioinformatic analyses were employed to map the immune landscape and predict potential regulatory mechanisms. These predictions were subsequently validated using in vitro cellular assays and in vivo mouse models. The unique lipid metabolic signature of TNBC was integrated with its distinct immune contexture to identify key regulators. Results The oxysterol metabolite 25-hydroxycholesterol (25HC) was identified as a key regulator of macrophage polarization. Specifically, we discovered that an aberrantly activated interferon regulatory factor 7–cholesterol-25-hydroxylase–25HC axis in TNBC cells potently inhibits CD163 + macrophage polarization. Discussion To our knowledge, this is the first study to delineate the link between dysregulated 25HC metabolism within the TIME and the control of macrophage polarization. These findings provide novel insights into the immunometabolic mechanisms underlying TNBC aggressiveness and reveal a potential therapeutic target for this devastating disease.
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