T-Dxd is the 2nd U.S. FDA-approved HER2-targeted ADC in metastatic HER2-positive BC and the first HER2-targeted agent in metastatic or inoperable HER2-low BC. It is composed of an anti-HER2 immunoglobulin G1 antibody, a tetrapeptide-based cleavable linker and a membrane permeable topoisomerase I inhibitor payload with a drug-to-antibody ratio of 8:1. A randomized phrase III, DB-04 trial evaluated T-Dxd in 557 patients (494 HR positive and 63 TNBCs) with HER2-low unresectable or metastatic BC previously treated with one or two lines chemotherapy [12]. Treatment with T-Dxd (5.4 mg/kg, every 3 weeks), in addition to chemotherapy of physician’s choice, resulted in a confirmed objective response rate of 52.6% in HR-positive patients and 52.3% in the overall study population compared to chemotherapy of physicians’ choice (16.3%). Compared to the chemotherapy of physician’s choices, T-Dxd significantly improved PFS in HR-positive patients (10.1 vs. 5.4 months, hazard ratio 0.51, ppp = 0.003) and the overall population (23.4 vs. 16.8 months, hazard ratio 0.64, p = 0.001). Similarily, in an exploratory analysis in a small number of patients with TNBCs, T-Dxd also improved PFS (8.5 vs. 2.9 months, hazard ratio 0.46) and OS (18.2 vs. 8.3 months, hazard ratio 0.48) [12].In contrast to other anti-HER2 agents, the unique clinical benefits of T-Dxd in HER2-low BC might be achieved by the so-called “bystander killing” mechanisms due to the highly membrane-permeable payload, high drug-to-antibody ratio and cleavable linker. An in vitro study has demonstrated that T-Dxd could induce a potent “bystander killing” effect on cells in close proximity to targeted HER2-expressing tumor cells by transferring the released payload into the neighboring cells, regardless of their HER2 status [79]. It appears that in HER2-low BC, HER2 molecules on the tumor cell surface primarily function as a means for delivering antibody conjugated drugs, instead of direct inhibition of HER2 dimerization or the blockade of downstream signaling [15].T-Dxd has generally manageable and tolerable safety profile with gastrointestinal disturbances, myelotoxicity, and alopecia being most common adverse effects. Approximately 28% of patients developed adverse reactions, and 16% of patients had to stop receiving the drug permanently during the clinical trial [80]. Interstitial lung disease (ILD)/pneumonitis is the most concerning adverse event associated with T-Dxd treatment. In a recent pooled analysis of 1150 patients who received one or more dose of ≥5.4 mg/kg T-Dxd monotherapy from nine phase I and II clinical trials, T-Dxd-related ILD/pneumonitis was found in 15.4% of patients, and most were low grade (77.4%, grade 1 or 2; 3.4% grade 3 and above) and occurred in the first 12 months of treatment [81]. Age 6.4 mg/kg, oxygen saturation 4 years are the factors of interest associated with any-grade adjudicated drug-related ILD/pneumonitis [81,82]. It needs to be mentioned that with the implementation of updated guidelines for the management of toxic effects in 2019, in the DB-04 trial, the numerical incidence of high-grade events (grade 3 and above) decreased to 2.1% [12]. The specific mechanism of lung injury by T-Dxd is not clear, although it was hypothesized that the ADC-induced alveolar damage is likely due to the target-independent uptake of the conjugated payload by immune cells [82,83]. During T-Dxd treatment, if patients develop dry cough, dyspnea, fever or other new or worsening respiratory symptoms, prompt clinical and imaging evaluation of potential ILD/pneumonitis is warranted [82,84], and permanent discontinuation of T-Dxd in patients with grade 2 or higher ILD/pneumonitis should be considered. Further work is needed to better understand the pathophysiology of T-Dxd-associated ILD/pneumonitis along with the delineation of risk factors, prevention, and treatment measures, ultimately to improve the safety profile of T-Dxd for treating HER2-low BC.