B7-H3 is an immune checkpoint molecule from the B7 superfamily. It has been widely studied in tumor immune evasion in certain types of cancer. In our preliminary study, we found that B7-H3 is specifically enriched in tumor-associated macrophages (TAMs) in triple-negative breast cancer (TNBC) patients and strongly correlated with poor clinical prognosis. However, the role of B7-H3 in breast cancer remains elusive. Our current study aims to explore the potential of B7-H3 as a novel target in TNBC therapy. Here, we demonstrated that B7-H3 enriched on TAMs is tightly correlated with TNBC clinical progression. B7-H3high TAMs exhibit great pro-metastatic and immunosuppressive functions by intriguing extracellular matrix (ECM) reconstruction and tumor angiogenesis, therefore helping tumor cell dissemination and dampening T-cell infiltration in tumor microenvironment (TME). Importantly, targeting blockade of B7-H3 by anti-B7-H3 antibody improves the tumor vasculature disorder, thereby enhancing chemotherapy and PD-1 therapy efficacy. In conclusion, our study establishes the correlation between B7-H3high TAMs and TNBC progression for the first time. By exploring the possibility of targeting B7-H3 expressed in both tumor cells and TAMs, we suggest that B7-H3 could be a promising target in clinical TNBC treatment.Keywords: Angiogenesis; B7-H3; Combination cancer therapy; TAMs; TNBC.