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

  • Nat Commun. 2025 Apr 2;16(1):3167. doi: 10.1038/s41467-025-58266-8.
Li-Chung Tsao  1 ,  John S Wang  2 ,  Xingru Ma  3 ,  Sirajbir Sodhi  2 ,  Joey V Ragusa  3 ,  Bushangqing Liu  4 ,  Jason McBane  1 ,  Tao Wang  1 ,  Junping Wei  1 ,  Cong-Xiao Liu  1 ,  Xiao Yang  1 ,  Gangjun Lei  1 ,  Ivan Spasojevic  2  5 ,  Ping Fan  5 ,  Timothy N Trotter  1 ,  Michael Morse  1  2 ,  Herbert Kim Lyerly  1  3  6 ,  Zachary C Hartman  7  8  9  10
Affiliations
  • 1. Department of Surgery, Duke University, Durham, NC, USA.
  • 2. Department of Medicine, Duke University, Durham, NC, USA.
  • 3. Department of Pathology, Duke University, Durham, NC, USA.
  • 4. Program in Cell and Molecular Biology, Duke University, Durham, NC, USA.
  • 5. PK/PD Core Laboratory, Duke Cancer Institute, Durham, NC, USA.
  • 6. Department of Integrative Immunobiology, Duke University, Durham, NC, USA.
  • 7. Department of Surgery, Duke University, Durham, NC, USA. [email protected].
  • 8. Department of Pathology, Duke University, Durham, NC, USA. [email protected].
  • 9. Program in Cell and Molecular Biology, Duke University, Durham, NC, USA. [email protected].
  • 10. Department of Integrative Immunobiology, Duke University, Durham, NC, USA. [email protected].
PMID: 40175391 DOI: 10.1038/s41467-025-58266-8
Abstract

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 efficiently cleaves the specialized linker of T-DXd, facilitating payload release and inducing cytotoxicity against HER2-low/negative tumors. In HER2-positive BC, the antibody backbone of T-DXd engages Fcγ-receptors and drives antibody-dependent cellular phagocytosis (ADCP). Concurrently, its cytotoxic payload (DXd) induces immunogenic cell death, further activating myeloid cells via TLR4 and STING pathways to enhance tumor antigen presentation to CD8+ T cells. Notably, T-DXd cytotoxicity also upregulates tumor CD47 expression, dampening immune activation. Combining T-DXd with CD47 checkpoint blockade significantly enhances anti-tumor immune responses in a HER2-transgenic BC mouse model, while also inducing durable CD8+ T cell memory to prevent tumor recurrence after therapy cessation.

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