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

Li-Chung Tsao, John S. Wang, Xingru Ma, Sirajbir Sodhi, Joey V. Ragusa, Bushangqing Liu, Jason McBane, Tao Wang, Junping Wei, Cong-Xiao Liu, Xiao Yang, Gangjun Lei, Ivan Spasojevic, Ping Fan, Timothy N. Trotter, Michael Morse, Herbert Kim Lyerly and Zachary C. Hartman ()
Additional contact information
Li-Chung Tsao: Duke University
John S. Wang: Duke University
Xingru Ma: Duke University
Sirajbir Sodhi: Duke University
Joey V. Ragusa: Duke University
Bushangqing Liu: Duke University
Jason McBane: Duke University
Tao Wang: Duke University
Junping Wei: Duke University
Cong-Xiao Liu: Duke University
Xiao Yang: Duke University
Gangjun Lei: Duke University
Ivan Spasojevic: Duke University
Ping Fan: Duke Cancer Institute
Timothy N. Trotter: Duke University
Michael Morse: Duke University
Herbert Kim Lyerly: Duke University
Zachary C. Hartman: Duke University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58266-8

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