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Peer-reviewedCC BYNature Biotechnology

Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors

  • Guolan Lu1,2
  • John W. Hickey3,4,5
  • Maximilian Haist6,4,5
  • Xulei Qin7
  • Dr. Emily Zhao8
  • Abdullah Naveed9,10
  • Erna Forgó11,5
  • Marc‐Andrea Baertsch12,13,4
  • Lucas Mani14,10
  • Xavier Rovira Clavé4,5,15
  • Andrey Finegersh14
  • Yury Goltsev4,5
14 more authors
  • Chiara Caraccio4,5
  • Nynke S. van den Berg14
  • Marisa E. Hom14,10
  • Deana R.C. Colburg5
  • Brock A. Martin5
  • Christina S. Kong5
  • Natalie S. Lui16
  • George Albert Fisher17
  • Alexander Dimitrios Colevas17
  • Robert B. West5
  • Greg M. Thurber18,19,20
  • George A. Poultsides7
  • Garry P. Nolan21,22
  • Eben Lloyd Rosenthal23,24
24 affiliations
  1. 1Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  2. 2Department of Urology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  3. 3Department of Biomedical Engineering, Duke University, Durham, NC, USA
  4. 4Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
  5. 5Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
  6. 6Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  7. 7Department of Surgery, Stanford University, Stanford, CA, USA
  8. 8Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
  9. 9Department of Otolaryngology, Tulane University School of Medicine, New Orleans, LA, USA
  10. 10Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA
  11. 11Department of Pathology, Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA
  12. 12Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center, Heidelberg, Germany
  13. 13Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
  14. 14Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA
  15. 15Institute for Bioengineering of Catalonia, Barcelona Institute of Science and Technology, Barcelona, Spain
  16. 16Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA
  17. 17Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, CA, USA
  18. 18Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
  19. 19Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA
  20. 20Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
  21. 21Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  22. 22Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  23. 23Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
  24. 24Department of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected]
Open at sourceDOICite

Abstract

The development of effective antibody therapeutics has been hampered by a lack of methods to measure drug delivery and activity within tumors at single-cell resolution. Here we introduce single-cell spatial pharmacobiology (SSP), an experimental and analytical framework that integrates in situ imaging of a systemically infused, fluorescently labeled therapeutic antibody with high-plex spatial proteomics to quantify antibody distribution, target engagement and tumor microenvironment (TME) architecture. We applied SSP to tumor tissues from participants with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma who received the antibody panitumumab-IRDye800 in phase 1 trials. SSP identified pronounced spatial heterogeneity in single-cell drug delivery and target engagement, shaped by conserved stromal barriers, including periostin-rich extracellular matrix assemblies and fibroblast-activation-protein-positive cancer-associated fibroblast neighborhoods, which were associated with reduced antibody delivery in both tumor types. SSP measures drug-target-TME interactions in human tumors and can support studies of resistance mechanisms, dosing strategies and discovery of spatial biomarkers for precision oncology.

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Cite

BibTeXRIS
BibTeX
@article{lu2026singlecell,
  title = {{Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors}},
  author = {Guolan Lu and John W. Hickey and Maximilian Haist and Xulei Qin and Dr. Emily Zhao and Abdullah Naveed and Erna Forgó and Marc‐Andrea Baertsch and Lucas Mani and Xavier Rovira Clavé and Andrey Finegersh and Yury Goltsev and Chiara Caraccio and Nynke S. van den Berg and Marisa E. Hom and Deana R.C. Colburg and Brock A. Martin and Christina S. Kong and Natalie S. Lui and George Albert Fisher and Alexander Dimitrios Colevas and Robert B. West and Greg M. Thurber and George A. Poultsides and Garry P. Nolan and Eben Lloyd Rosenthal},
  journal = {Nature Biotechnology},
  year = {2026},
  month = jun,
  doi = {10.1038/s41587-026-03152-x},
  url = {https://doi.org/10.1038/s41587-026-03152-x},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Single-cell spatial pharmacobiology identifies conserved stromal barriers to therapeutic antibody delivery in human solid tumors
AU  - Guolan Lu
AU  - John W. Hickey
AU  - Maximilian Haist
AU  - Xulei Qin
AU  - Dr. Emily Zhao
AU  - Abdullah Naveed
AU  - Erna Forgó
AU  - Marc‐Andrea Baertsch
AU  - Lucas Mani
AU  - Xavier Rovira Clavé
AU  - Andrey Finegersh
AU  - Yury Goltsev
AU  - Chiara Caraccio
AU  - Nynke S. van den Berg
AU  - Marisa E. Hom
AU  - Deana R.C. Colburg
AU  - Brock A. Martin
AU  - Christina S. Kong
AU  - Natalie S. Lui
AU  - George Albert Fisher
AU  - Alexander Dimitrios Colevas
AU  - Robert B. West
AU  - Greg M. Thurber
AU  - George A. Poultsides
AU  - Garry P. Nolan
AU  - Eben Lloyd Rosenthal
PY  - 2026
DA  - 2026/06/03
JO  - Nature Biotechnology
DO  - 10.1038/s41587-026-03152-x
UR  - https://doi.org/10.1038/s41587-026-03152-x
AB  - The development of effective antibody therapeutics has been hampered by a lack of methods to measure drug delivery and activity within tumors at single-cell resolution. Here we introduce single-cell spatial pharmacobiology (SSP), an experimental and analytical framework that integrates in situ imaging of a systemically infused, fluorescently labeled therapeutic antibody with high-plex spatial proteomics to quantify antibody distribution, target engagement and tumor microenvironment (TME) architecture. We applied SSP to tumor tissues from participants with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma who received the antibody panitumumab-IRDye800 in phase 1 trials. SSP identified pronounced spatial heterogeneity in single-cell drug delivery and target engagement, shaped by conserved stromal barriers, including periostin-rich extracellular matrix assemblies and fibroblast-activation-protein-positive cancer-associated fibroblast neighborhoods, which were associated with reduced antibody delivery in both tumor types. SSP measures drug-target-TME interactions in human tumors and can support studies of resistance mechanisms, dosing strategies and discovery of spatial biomarkers for precision oncology.
SN  - 0733-222X
SN  - 1087-0156
SN  - 1546-1696
SN  - 2331-3684
ER  -