Integrated metabolomics of tumor and plasma reveals local and systemic metabolic responses to T-DM1 therapy

Comprehensive mapping of drug-induced metabolic alterations is crucial for understanding the mechanisms of targeted therapies. Antibody–drug conjugates (ADCs) such as trastuzumab emtansine (T-DM1) have revolutionized targeted cancer therapy by combining antibody specificity with cytotoxic potency. However, the metabolic reprogramming underlying their therapeutic action and systemic effects remains poorly understood. Here, we applied high-performance liquid chromatography–mass spectrometry (HPLC–MS)-based metabolomics to profile tumor and plasma metabolic alterations in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model at 4- and 7-days following T-DM1 treatment, corresponding to the period of pronounced antitumor activity. A total of 32 significantly altered metabolites were identified in tumor tissues, mapping to pathways including tricarboxylic acid (TCA) cycle, pyrimidine metabolism and lipid metabolism, reflecting disruption in energy production and macromolecular biosynthesis. In plasma, 12 significantly altered metabolites were identified, predominantly affecting histidine, glutamine, taurine, tryptophan, and tyrosine metabolism. Integrated analysis further revealed two compartment-specific metabolites—hippuric acid and uric acid—showing opposite trends, with elevated levels in tumors and reduced levels in plasma. These bidirectional changes indicate a metabolic coupling between tumor and circulation, driven by differential utilization and excretion processes during T-DM1 response. Collectively, our findings demonstrate that T-DM1 elicits coordinated local and systemic metabolic reprogramming, providing mechanistic insights into its antitumor activity and the metabolic coupling between tumor and circulation.