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Triple-negative breast cancer (TNBC) is an aggressive and molecularly heterogeneous subtype of breast cancer characterized by limited targeted treatment options, frequent chemoresistance, and a strong propensity for metastasis, particularly to the central nervous system (CNS). These challenges highlight the need for multi-targeted therapeutic strategies. The tumor-targeting peptide p28, which exhibits antitumor activity and potential blood-brain barrier (BBB) penetration, represents a promising candidate for enhancing therapeutic efficacy in TNBC through distinct mechanisms of action. In this study the effects of p28, five standard chemotherapeutic agents, and their low-dose combinations with p28 were systematically evaluated in TNBC models in vitro and in vivo. Cellular responses, including BBB permeability, viability, proliferation, apoptosis, cell cycle distribution, oxidative stress, DNA damage, and metastatic potential, were assessed. Integrated transcriptomic and systems biology analyses were performed to identify dysregulated pathways, and selected targets were subsequently evaluated at the transcript and protein levels. In xenograft models, tumor growth, apoptosis, metastasis-related features, histopathology, toxicity, and overall survival were comprehensively assessed. p28 reduced TNBC cell viability while sparing normal cells, demonstrated favorable BBB permeability, and significantly enhanced the antitumor activity of chemotherapeutic agents at reduced doses. These combinations showed synergistic effects, resulting in markedly enhanced tumor suppression, increased apoptosis, reduced invasion and metastasis, reduced toxicity, and prolonged survival. Collectively, these findings support p28 as a promising preclinical combination strategy in TNBC, distinguished by its synergistic interaction with chemotherapy, and justify further investigation of its therapeutic potential in metastatic breast cancer.