<p>Metastatic breast cancer, particularly triple-negative breast cancer (TNBC), remains a major clinical challenge due to its aggressive behavior and limited therapeutic options. The molecular pathways that drive tumor progression while simultaneously promoting immune evasion are not well defined. Here, we identify S100A7/RAGE signaling as a central oncogenic and immunomodulatory axis that drives TNBC tumorigenicity, metastasis, and immune suppression. In this study, we have shown that S100A7/RAGE signaling plays a vital role in driving invasive TNBC tumorigenicity by activating Stat3 and elevating Serpin-E1 expression. Furthermore, we revealed that combinatorial treatment of Stat3 and RAGE inhibitors synergistically inhibits the tumorigenicity of S100A7-expressing TNBC cells in-vitro by suppressing AKT/MAPK signaling and mitigates the tumor burden, especially distant metastasis in-vivo using TNBC cell lines and a conditional mammary gland-specific S100A7 overexpression bitransgenic mouse model. Moreover, our study also shed light on the dynamic interplay between the S100A7/RAGE/Stat3 signaling pathway and immune cell infiltration within the tumor microenvironment. Remarkably, our findings underscored the potential of combined inhibition to enhance anti-tumor immune responses, fostering the infiltration of anti-tumor MHCII^high and iNOS⁺ macrophages and activated effector CD8⁺ tumor-infiltrating T cells. Moreover, CD8⁺ 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.</p> Graphical abstract <p></p>