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Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging subtype defined by the absence of estrogen receptor, progesterone receptor, and HER2 amplification, resulting in poor prognosis and limited therapeutic options. Targeting alternative molecular pathways is urgently needed to overcome resistance and improve patient outcomes. CD147 has emerged as surface marker associated with tumor progression and immune evasion. In this study, CD147 and MHC class I-a key inhibitory ligand for natural killer cells-were analyzed in breast cancer cell lines (MCF7, MDA-MB-453, MDA-MB-231, and HCC38) using flow cytometry. The therapeutic efficacy of a humanized anti-CD147 monoclonal antibody (HuM6-1B9) was evaluated for its capacity to potentiate antibody-dependent cellular cytotoxicity (ADCC). HuM6-1B9 demonstrated the strong binding to MDA-MB-231 (K_D = 4.982 nM) and HCC38 (K_D = 4.523 nM), which are representative TNBC cell lines. In 3D spheroid models, HuM6-1B9 significantly enhanced PBMC-mediated ADCC, leading to a marked reduction in TNBC spheroid viability. Co-culture of CFSE-labeled MDA-MB-231 and HCC38 cells with primary NK cells confirmed robust ADCC, achieving 50% and 70% cytotoxicity, respectively, despite high MHC class I expression. Live-cell imaging demonstrated caspase-3/7 activation consistent with apoptosis in NK-targeted tumor cells, while CD107a degranulation and IFN-γ secretion confirmed the functional contribution of HuM6-1B9 to ADCC enhancement. Importantly, HuM6-1B9 did not promote migration or invasion in MDA-MB-231 cells, supporting its safety profile regarding metastasis. Collectively, these findings establish HuM6-1B9 as a promising immunotherapeutic candidate that overcomes immune resistance and selectively eliminates TNBC cells through ADCC without enhancing metastatic potential. By integrating mechanistic assays of NK cytotoxicity, apoptosis, and 3D tumor spheroids, this study provides clinically relevant insights underscoring the translational potential of HuM6-1B9 in TNBC immunotherapy.