Rationale: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. There are very few targeted treatment options with satisfactory therapeutic indexes for TNBC. Although chemotherapy is the principal treatment modality for TNBC, its effectiveness is significantly compromised by low chemosensitivity in the TNBC patient population. Recent evidence has suggested that metabolic adaptation of tumor cells may play a critical role in reducing therapeutic responses. Metabolic interventions could enhance chemosensitivity and improve chemotherapeutic efficacy. Methods: The influence of oxidative phosphorylation (OXPHOS) on TNBC chemosensitivity was evaluated by integrating bioinformatic analyses of patient datasets with metabolic phenotyping of TNBC cells. The correlation was established between the level of OXPHOS gene expression and therapeutic responses to standard chemotherapeutics. A mitochondria-targeting OXPHOS inhibitor, TPP-LND (a mitochondria-targeting derivative of lonidamine), was synthesized. A dendron-based polymer was conjugated with epirubicin (EPI) via an acid-responsive hydrazone bond to form a nanocarrier. TPP-LND was subsequently encapsulated into this nanocarrier, yielding PEG-Dendron-EPI@TPP-LND. Results: In TCGA-BRCA cohorts, an elevation in OXPHOS gene expression was correlated with poor clinical outcomes and a higher IC50 value of chemotherapeutic drugs like EPI was found in the patients with upregulated OXPHOS expression, suggesting diminished chemosensitivity in these patients. TNBC cells heavily relied on mitochondrial ATP production, and TPP-LND effectively inhibited OXPHOS. PEG-Dendron-EPI@TPP-LND significantly suppressed tumor growth and prevented compensatory glycolytic activation without inducing observable systemic toxicity in vivo. Conclusion: A mechanistic correlation was established between the OXPHOS activity and TNBC chemosensitivity. OXPHOS inhibition via TPP-LND was synergized with chemotherapy via the EPI prodrug to effectively suppress tumor growth and mitigate systemic toxicity of TPP-LND and EPI. This strategy could be promising for metabolic interventions to enhance the efficacy of chemotherapy in TNBC.© The author(s).