Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd)

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2, exhibiting significant clinical efficacy in breast cancer (BC) with varying HER2 expression, including HER2-low and HER2-ultralow. However, the precise mechanism underlying its efficacy and the contribution of immune activation in these settings remain unclear. Here, we demonstrate that T-DXd efficacy in HER2-low and HER2-negative BC is independent of HER2 engagement and ADC internalization. Instead, its activity relies on extracellular proteases, such as cathepsin L (CTSL), within the tumor microenvironment. Irrespective of their HER2 status, tumor and stromal compartments of invasive BC abundantly express CTSL, which…

• UD
  U.S. Department of Defense

  Awards: BC191055, W81XWH, W81XWH-16-1-0354, BC201085
• SG
  Susan G. Komen
• NI
  National Institutes of Health

  Awards: P30CA014236, R01CA238217-01A1/02S1, W81XWH
• NC
  National Cancer Institute

  Award: P30CA014236