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Targeting the tumour cell surface in advanced prostate cancer

Nature Reviews Urology volume 22, pages 569–589 (2025)Cite this article

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Abstract

Prostate cancer remains a substantial health challenge, with >375,000 annual deaths amongst men worldwide. Most prostate cancer-related deaths are attributable to the development of resistance to standard-of-care treatments. Characterization of the diverse and complex surfaceome of treatment-resistant prostate cancer, combined with advances in drug development that leverage cell-surface proteins to enhance drug delivery or activate the immune system, have provided novel therapeutic opportunities to target advanced prostate cancer. The prostate cancer surfaceome, including proteins such as prostate-specific membrane antigen (PSMA), B7-H3, six transmembrane epithelial antigen of the prostate 1 (STEAP1), delta-like ligand 3 (DLL3), trophoblastic cell-surface antigen 2 (TROP2), prostate stem cell antigen (PSCA), HER3, CD46 and CD36, can be exploited as therapeutic targets, as regulatory mechanisms might contribute to the heterogeneity of expression of these proteins and subsequently affect treatment response and resistance. Specific treatment strategies targeting the surfaceome are in clinical development, including radionuclides, antibody–drug conjugates, T cell engagers and chimeric antigen receptor (CAR) T cells. Ultimately, biomarker development and clinical implementation of these agents will be informed and refined by further understanding of the biology of various targets; the target specificity and sensitivity of different agents; and off-target and toxic effects associated with these agents. Understanding the dynamic nature of cell-surface targets and non-overlapping expression patterns might also lead to future combinational strategies.

Key points

  • Surface proteins such as prostate-specific membrane antigen (PSMA), B7-H3, six transmembrane epithelial antigen of the prostate 1 (STEAP1), delta-like ligand 3 (DLL3), trophoblastic cell-surface antigen 2 (TROP2), prostate stem cell antigen (PSCA), HER3 and CD46 are a promising class of novel therapeutic targets in prostate cancer.

  • Radioligand therapies consist of antibodies or small molecules conjugated to radioactive isotopes to deliver targeted radiation. Advances in PSMA imaging and PSMA-targeted radioligands (such as [177Lu]-PSMA-617) have led to improved outcomes in metastatic castration-resistant prostate cancer. Other radioligand therapies are in development.

  • Antibody–drug conjugates consist of an antigen-specific antibody, a chemical linker and a cytotoxic payload, which enable targeted delivery of chemotherapy while minimizing systemic toxicity. Several antibody–drug conjugates are under investigation in prostate cancer, with challenges including stability, toxicity and resistance mechanisms.

  • Targeted T cell engager and chimeric antigen receptor T cell therapies are designed to overcome the limited efficacy of targeting non-specific immune checkpoints in prostate cancer. These new immune strategies are focused on balancing immune activation and antitumour activity while minimizing toxicity associated with excessive immune stimulation.

  • Broad challenges in targeting cell-surface proteins include tumour heterogeneity and dynamic target expression; patient-specific tumour, host and drug features that might limit efficacy; and the development of acquired resistance mechanisms including loss of target expression.

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Fig. 1: Crucial characteristics of cell-surface targets.
Fig. 2: General assembly of radioligands and antibody–drug conjugates.

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Acknowledgements

The authors apologize to the many researchers whose work we were unable to cite because of space limitations. We thank members of the Beltran and de Bono lab for discussion of topics relevant to this Review. V.B.V. is supported by the DoD PCRP Early Investigator Research Award (W81XWH2210197), the National Cancer Center Postdoctoral Fellowship Award and the Prostate Cancer Foundation Young Investigator Award (23YOUN15). H.B. is supported by the Prostate Cancer Foundation, the DoD PCRP (W81XWH-17-1-0653) and the NIH/NCI (R37CA241486-01A1, DF/HCC SPORE P50 CA272390-01, WCM SPORE P50 CA211024-01A1). The de Bono laboratory acknowledges funding from Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, the Medical Research Council and the US Department of Defense.

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Author notes

  1. These authors contributed equally: Cristina Boixareu, Tarek Taha, Varadha Balaji Venkadakrishnan.

Authors and Affiliations

  1. The Institute of Cancer Research, The Royal Marsden Hospital, London, UK

    Cristina Boixareu, Tarek Taha & Johann de Bono

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Varadha Balaji Venkadakrishnan & Himisha Beltran

  3. Harvard Medical School, Boston, MA, USA

    Varadha Balaji Venkadakrishnan & Himisha Beltran

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  1. Cristina Boixareu
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  4. Johann de Bono
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  5. Himisha Beltran
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The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Johann de Bono or Himisha Beltran.

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Competing interests

H.B. has served as consultant/advisory board member for Janssen, AstraZeneca, Merck, Pfizer, Amgen, Bayer, Daiichi Sankyo and Novartis, and has received research funding (to their institution) from Janssen, Bristol Myers Squibb, Circle Pharma, Daiichi Sankyo and Novartis. J.d.B. has served as an adviser for Daiichi Sankyo, AstraZeneca, MSD, Pfizer, Amgen, Bayer, Merck Serono, Janssen, GSK, Macrogenics, Actinium Pharma, Astellas, Amunix and Sanofi-Aventis. The other authors declare no competing interests.

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Nature Reviews Urology thanks Lawrence True, Naga Vara Kishore Pillarsetty and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Boixareu, C., Taha, T., Venkadakrishnan, V.B. et al. Targeting the tumour cell surface in advanced prostate cancer. Nat Rev Urol 22, 569–589 (2025). https://doi.org/10.1038/s41585-025-01014-w

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