ObjectiveTo analyze the clinical repositioning and individualized treatment strategies of trastuzumab emtansine (T-DM1) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the era of trastuzumab deruxtecan (T-DXd). MethodsThe latest evidence-based data for T-DM1 were systematically reviewed to identify two optimized clinical approaches: intensified combination therapy and de-escalation. For advanced and brain metastastic HER2-positive breast cancer, the synergistic antitumor efficacy of T-DM1 combined with tyrosine kinase inhibitors, along with data from pivotal trials such as HER2CLIMB-02, was analyzed. For early-stage HER2-positive breast cancer, the feasibility of chemotherapy-free de-escalation regimens was evaluated based on the WSG-ADAPT trial and other relevant studies. ResultsThe differentiated value of T-DM1 is defined by its lower risk of interstitial lung disease and established long-term survival benefit, as evidenced by the 7-year invasive disease-free survival (iDFS) rate of 80.8% reported in the KATHERINE trial. Regarding intensified combinations, exploratory analyses of the KATE2 trial revealed synergistic potential of T-DM1 plus immune checkpoint inhibitors in the programmed death-ligand 1-positive subgroup. In patients with brain metastastatic HER2-positive, the HER2CLIMB-02 study confirmed a median progression-free survival benefit by adding tucatinib to T-DM1 [HR (95%CI)=0.64 (0.46, 0.89)]. In terms of de-escalation, the WSG-ADAPT trial reported a 5-year iDFS rate of 92.1% with chemotherapy-free regimens in molecularly selected populations. Additionally, the “decoupling” of pathological complete response from long-term outcomes observed in the KRISTINE trial provides biological rationale for de-escalation strategies, interpreted through the lenses of immune memory and senescence-associated tumor cell fate. Moreover, the sequential switching strategy—grounded in the non-cross-resistant payload mechanism—and the clinical accessibility brought by T-DM1’s inclusion in China’s National Reimbursement Drug List serve as additional dimensions supporting its clinical repositioning. ConclusionsIn the era of T-DXd, clinical decision-making regarding T-DM1 for HER2-positive breast cancer is shifting toward risk-stratified, precision-based management. The core strategic framework comprises an intensified combination pathway for patients with brain metastases and a de-escalation pathway for those with toxicity-driven de-escalation. However, specific implementation still requires comprehensive evaluation tailored to individual patient characteristics, biomarker profiles, and drug accessibility.