MRO/HNRNPU/CCL5 feedback loop amplifies M2 macrophage and breast cancer cell crosstalk to drive progression.

BACKGROUND

M2 macrophages are known to enhance the malignant phenotype of breast cancer (BC) cells, yet the underlying mechanisms remain unclear.

METHODS

scRNA sequencing analysis, chromatin immunoprecipitation, immunoprecipitation, exosome isolation, and biological experiments were used to analyze this crosstalk.

RESULTS

Maestro (MRO) was involved in the crosstalk between M2 macrophages and BC cells. MRO expression was elevated in BC tissues, particularly in those with high CD68 and CD206 expression, and correlated with poor prognosis. MRO was highly expressed in M2 macrophages, and its mRNA was transferred from M2 macrophages to BC cells via exosomes. Engineering exosomes with MRO knockdown demonstrated reduced tumor-promoting effects compared to controls. Mechanistically, MRO in BC cells functioned as a nuclear import protein, facilitating the translocation of HNRNPU into the nucleus. HNRNPU then enhanced CCL5 transcription by binding to its promoter. Elevated CCL5 not only promoted BC cell malignancy, but also recruited more macrophages and induced M2 polarization.

CONCLUSIONS

These findings reveal a novel MRO/HNRNPU/CCL5 feedback loop in the interaction between M2 macrophages and BC cells, driving BC progression and reshaping the tumor microenvironment. Targeting this feedback loop offers a potential therapeutic strategy for BC.