Research Reports:
Cell Stress, Vol. 9, No. 1, pp. 194 - 200; doi: 10.15698/cst2025.08.311
Datopotamab deruxtecan induces hallmarks of immunogenic cell death
1 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France. 2 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université Paris Cité, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France. 3 Institut du Cancer Paris CARPEM, Department of Biology, APHP, Hôpital Européen Georges Pompidou, Paris, France.
Keywords: anticancer immunotherapy, antibody drug conjugate, bystander effect.
Received originally: 03/07/2025 Received in revised form: 28/07/2025
Accepted: 29/07/2025
Published: 11/08/2025
Correspondence:
Dr. Oliver Kepp, captain.olsen@gmail.com
Prof. Dr. Guido Kroemer, kroemer@orange.fr
Conflict of interest statement:
Please cite this article as: Sabrina Forveille, Marion Leduc, Allan Sauvat, Guido Kroemer and Oliver Kepp (2025). Datopotamab deruxtecan induces hallmarks of im-munogenic cell death. Cell Stress 9: 194-200. doi: 10.15698/cst2025.08.311
Abstract
Antibody-drug conjugates (ADCs) offer a strategy for targeted delivery of cytotoxic agents to cancer cells. In this study, we investigated the mechanism of action of datopotamab deruxtecan, an ADC composed of a monoclonal antibody targeting tumor-associated calcium signal transducer 2 (TACSTD2, also known as trophoblast cell-surface antigen-2 (TROP2)) conjugated to the topoisomerase I inhibitor DXd. Datopotamab deruxtecan reduced the viability of human osteosarcoma U2OS cells engineered to express TROP2, but had no effect on their parental counterparts, which only expressed the CALR-GFP biosensor. In TROP2-expressing cells, it triggered the translocation of CALR-GFP from the ER to the cell periphery. Both datopotamab deruxtecan and its DXd payload elicited several features characteristic of immunogenic cell death (ICD), including detectable calreticulin exposure on the cell surface, release of high-mobility group box 1 (HMGB1), and ATP secretion into the culture medium. Importantly, the TROP2-targeted ADC also exerted a bystander antitumor effect on parental U2OS cells (lacking TROP2 expression) co-cultured with TROP2-expressing U2OS cells. These findings demonstrate that datopotamab deruxtecan delivers a cytotoxic payload capable of inducing hallmark features of ICD in vitro.
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ACKNOWLEDGMENTS
OK is supported by Association pour la recherche sur le cancer (ARC), Institut National du Cancer (INCa) and the European Innovation Council (EIC). G.K. is supported by the Ligue contre le Cancer (équipe la-bellisée); Agence National de la Recherche (ANR) - Projets blancs; AMMICa US23/CNRS UMS3655; ARC; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen (ANR 21-ESRE-0028); European Joint Programme on Rare Diseases (EJPRD); European Research Council Advanced Investigator Award (ERC-2021-ADG, ICD-Cancer, Grant No. 101052444), European Union Horizon 2020 Projects Oncobiome, Prevalung (grant No. 101095604) and Crimson (No. 101016923); Fondation Carrefour; INCa; Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM).
COPYRIGHT
© 2025
Datopotamab deruxtecan induces hallmarks of immunogenic cell death by Forveille et al. is licensed under a Creative Commons Attribution 4.0 International License.
