Commentary on "Targeting B7-H3 inhibition-induced activation of fatty acid synthesis boosts anti-B7-H3 immunotherapy in triple-negative breast cancer".

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by limited treatment options and poor prognosis. Immune checkpoint blockade, particularly via programmed cell death protein-1/programmed death-ligand 1 inhibition, has improved outcomes in selected patients with TNBC; however, resistance remains a major barrier. Recent studies have identified B7-H3 (CD276) as a key immune-suppressive molecule overexpressed in TNBC, correlating with poor prognosis and immune exclusion. Jiang et al demonstrate that B7-H3 inhibition triggers a compensatory metabolic adaptation in TNBC cells, marked by upregulation of fatty acid synthesis and β-oxidation, particularly via the AKT-SREBP1-FASN signaling axis. This metabolic reprogramming promotes survival and immune evasion, limiting the efficacy of B7-H3-targeted therapies. Dual inhibition of B7-H3 and fatty acid synthase synergistically enhances tumor cell apoptosis, suppresses proliferation and migration, and promotes CD8+ T-cell infiltration in vitro and in vivo. These findings reveal a novel immune-metabolic resistance mechanism in TNBC and provide a compelling rationale for combinatorial strategies targeting both immune checkpoints and metabolic pathways.