2. Academic Validation
  3. Effective extracellular payload release and immunomodulatory interactions govern the therapeutic effect of trastuzumab deruxtecan (T-DXd)

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

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. zachary.hartman@duke.edu.
  • 8 Department of Pathology, Duke University, Durham, NC, USA. zachary.hartman@duke.edu.
  • 9 Program in Cell and Molecular Biology, Duke University, Durham, NC, USA. zachary.hartman@duke.edu.
  • 10 Department of Integrative Immunobiology, Duke University, Durham, NC, USA. zachary.hartman@duke.edu.
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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