Triple-negative breast cancer remodeling of the tissue immune microenvironment by regulation of embryonic-derived tissue-resident macrophage polarization through the IRF7/CH25H/25HC pathway.

e14557 Background: The immune microenvironment of breast cancer is richly infiltrated with macrophages, yet modulation targeting macrophage polarization has failed to achieve significant clinical efficacy. Methods: We applied techniques such as parabiosis mouse models, multicolor immunofluorescence, bone marrow transplantation models and flow cytometry to explore in depth the characteristics of the immune microenvironment of breast cancer as well as the mechanisms of origin and replenishment of tissue-resident macrophages. Results: We found two interesting conclusions. Firstly, triple-negative breast cancer, which is considered to be one of the most biologically malignant subtypes, instead has a significantly reduced M2-like infiltration, and secondly, about 40% of the tissue-resident macrophages within the mammary tissues are derived from the embryonic lineage and exhibit a long lifecycle, proliferative and pluripotent properties. Through single-cell sequencing, we further found that the abnormally high expression status of IRF7/CH25H/25HC in triple-negative breast cancers remodeled the immune microenvironment of triple-negative breast cancers by regulating the expression levels of MHC and PD-1 in macrophages, especially targeting macrophages of embryonic lineage origin to play a significant regulatory role. Conclusions: The in-depth exploration and specific regulation of macrophage source and replenishment mechanisms are expected to be an effective modulator for regulating macrophage polarization within the TNBC immune microenvironment as well as anti-PD-1 therapy.