Therapeutic targeting of RAGE/STAT3 signaling abrogates S100A7-driven breast tumorigenicity and immune suppression.

T cells depletion abrogates the therapeutic benefits of RAGE/Stat3 inhibition by restoring the tumor growth in S100A7 overexpression mice. Importantly, we discovered that S100A7/RAGE signaling modulates anti-tumor macrophage phenotypes by regulating Serpin-E1 expression on TNBC cells. S100A7 regulates Serpin-E1 gene expression by enhancing the direct binding of pStat3 (Ser727) to its promoter. Notably, neutralization of Serpin-E1 in combination with RAGE and Stat3 inhibition increased iNOS expression in macrophages in-vitro and significantly enhanced overall anti-metastatic efficacy in-vivo. Importantly, we found that increased co-expression of S100A7 and Serpin-E1 correlated with worse prognoses in TNBC patients, whereas the presence of iNOS or MHCII genes improved the overall prognosis, especially basal and immunomodulatory subtypes, which also underscores the clinical relevance of targeting these signaling molecules as a promising translational therapeutic strategy for TNBC. Overall, these findings provide new avenues for therapeutic interventions in metastatic TNBC.