BACKGROUND: Triple-negative breast cancer (TNBC) is the most malignant breast cancer, highlighting the need for effective immunotherapeutic targets. The immune checkpoint molecule B7-H3 has recently gained attention as a promising therapeutic target due to its pivotal role in promoting tumorigenesis and cancer progression. However, the therapeutic impact of B7-H3 inhibitors (B7-H3i) remains unclear. METHODS: Transcriptomic and metabolomic analyses were conducted to explore the underlying mechanisms of B7-H3 inhibition in TNBC. The therapeutic efficacy of the combined treatment strategy was substantiated through comprehensive phenotypic assays conducted in vitro and validated in vivo using animal models. RESULTS: B7-H3 blockade induces a "primed for death" stress state in cancer cells, leading to distinct alterations in metabolic pathways. Specifically, B7-H3 knockdown activated the AKT signaling pathway and upregulated sterol regulatory element-binding protein 1 (SREBP1), which in turn elevated FASN expression. The simultaneous inhibition of both B7-H3 and FASN more effectively attenuated the malignant progression of TNBC. CONCLUSIONS: Our findings propose an "immune attack-metabolic compensation" dynamic model and suggest the feasibility of a dual-targeting strategy that concurrently inhibits both B7-H3 and FASN to enhance therapeutic efficacy in TNBC patients.