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Peer-reviewedCC BY-NC-ND 4.0Cancer Research

Spatial Profiling Reveals Immune Escape Pathways and Therapeutic Vulnerabilities in Prostate Cancer Bone Metastases

  • Katie L. Owen1,2
  • Linden J. Gearing3,4,5
  • Birunthi Niranjan6
  • Madawa Jayawardana1,2
  • Thomas B. Chadwick1,2
  • Holly I. Newman1
  • Sirui Weng1,2
  • Anna S. Trigos1,2,7,8
  • Lisa M. Devereux1,2
  • Bethany K. Campbell9,10,11
  • Anupama Pasam1
  • Niall M. Corcoran9,10,11,12
6 more authors
  • Renea A. Taylor2,13,14
  • Christopher M. Hovens9,10
  • Paul J. Hertzog3,4
  • Shahneen Sandhu2,15
  • Nicole M. Haynes1,2
  • Belinda S. Parker1,2
15 affiliations
  1. 1Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
  2. 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
  3. 3Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia.
  4. 4Department of Molecular and Translational Science, Monash University, Clayton, Australia.
  5. 5Immunobiology of Inflammation Group, German Rheumatology Research Center (DRFZ), an Institute of the Leibniz Association, Berlin, Germany.
  6. 6Prostate Cancer Research Group, Cancer Program, Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia.
  7. 7St.Vincent’s Institute of Medical Research, Fitzroy, Australia.
  8. 8Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Australia.
  9. 9Department of Urology, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia.
  10. 10Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia.
  11. 11Collaborative Centre for Cancer Genomic Medicine, Victorian Comprehensive Cancer Centre, University of Melbourne, Parkville, Australia.
  12. 12Department of Urology, Frankston Hospital, Frankston, Australia.
  13. 13Prostate Cancer Research Group, Cancer Program, Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia.
  14. 14Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
  15. 15Department of Medical Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Australia.
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Abstract

Prostate cancer frequently metastasizes to bone, marking incurable disease. This progression is driven by an immunologically cold bone tumor microenvironment that fosters resistance to therapy. To define the mechanisms underlying this uniquely immunosuppressive niche, we applied spatial single-cell analyses across primary tumors and metastatic sites. Bone metastases showed marked suppression of tumor-intrinsic type I interferon (IFN-I) signaling and loss of antigen presentation, features that were strongly associated with reduced bone metastasis-free survival. Tumor-intrinsic IFN-I expression correlated with memory T-cell infiltration, whereas the bone myeloid compartment was enriched for protumor macrophages and showed reduced dendritic cell activation and antigen presentation. Digital spatial profiling of matched tumors revealed a broad loss of IFN-I-regulated immunostimulatory and checkpoint molecules. Notably, B7-H3, a putative negative regulator of IFN-I, was highly expressed in bone metastases and inversely associated with antigen presentation. These findings define bone-specific mechanisms of immune resistance and highlight therapeutic vulnerabilities that could inform precision therapeutic strategies for prostate cancer.

Significance:: Prostate cancer bone metastases establish a tumor-driven, immunosuppressive niche featuring global impairment of IFN-I signaling and antigen presentation coupled to elevated B7-H3, highlighting clinically actionable vulnerabilities in advanced prostate cancer.

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Cite

BibTeXRIS
BibTeX
@article{owen2026spatial,
  title = {{Spatial Profiling Reveals Immune Escape Pathways and Therapeutic Vulnerabilities in Prostate Cancer Bone Metastases}},
  author = {Katie L. Owen and Linden J. Gearing and Birunthi Niranjan and Madawa Jayawardana and Thomas B. Chadwick and Holly I. Newman and Sirui Weng and Anna S. Trigos and Lisa M. Devereux and Bethany K. Campbell and Anupama Pasam and Niall M. Corcoran and Renea A. Taylor and Christopher M. Hovens and Paul J. Hertzog and Shahneen Sandhu and Nicole M. Haynes and Belinda S. Parker},
  journal = {Cancer Research},
  year = {2026},
  month = aug,
  doi = {10.1158/0008-5472.can-26-2386},
  url = {https://doi.org/10.1158/0008-5472.can-26-2386},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Spatial Profiling Reveals Immune Escape Pathways and Therapeutic Vulnerabilities in Prostate Cancer Bone Metastases
AU  - Katie L. Owen
AU  - Linden J. Gearing
AU  - Birunthi Niranjan
AU  - Madawa Jayawardana
AU  - Thomas B. Chadwick
AU  - Holly I. Newman
AU  - Sirui Weng
AU  - Anna S. Trigos
AU  - Lisa M. Devereux
AU  - Bethany K. Campbell
AU  - Anupama Pasam
AU  - Niall M. Corcoran
AU  - Renea A. Taylor
AU  - Christopher M. Hovens
AU  - Paul J. Hertzog
AU  - Shahneen Sandhu
AU  - Nicole M. Haynes
AU  - Belinda S. Parker
PY  - 2026
DA  - 2026/08/11
JO  - Cancer Research
DO  - 10.1158/0008-5472.can-26-2386
UR  - https://doi.org/10.1158/0008-5472.can-26-2386
AB  - Prostate cancer frequently metastasizes to bone, marking incurable disease. This progression is driven by an immunologically cold bone tumor microenvironment that fosters resistance to therapy. To define the mechanisms underlying this uniquely immunosuppressive niche, we applied spatial single-cell analyses across primary tumors and metastatic sites. Bone metastases showed marked suppression of tumor-intrinsic type I interferon (IFN-I) signaling and loss of antigen presentation, features that were strongly associated with reduced bone metastasis-free survival. Tumor-intrinsic IFN-I expression correlated with memory T-cell infiltration, whereas the bone myeloid compartment was enriched for protumor macrophages and showed reduced dendritic cell activation and antigen presentation. Digital spatial profiling of matched tumors revealed a broad loss of IFN-I-regulated immunostimulatory and checkpoint molecules. Notably, B7-H3, a putative negative regulator of IFN-I, was highly expressed in bone metastases and inversely associated with antigen presentation. These findings define bone-specific mechanisms of immune resistance and highlight therapeutic vulnerabilities that could inform precision therapeutic strategies for prostate cancer.  Significance:: Prostate cancer bone metastases establish a tumor-driven, immunosuppressive niche featuring global impairment of IFN-I signaling and antigen presentation coupled to elevated B7-H3, highlighting clinically actionable vulnerabilities in advanced prostate cancer.
SN  - 0008-5472
SN  - 1538-7445
ER  -