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Synergistic targeting strategies for prostate cancer

Nature Reviews Urology volume 22, pages 645–671 (2025)Cite this article

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Abstract

Prostate cancer is the second most commonly diagnosed cancer and the fifth leading cause of death among men worldwide. Androgen deprivation therapy is a common prostate cancer treatment, but its efficacy is often hindered by the development of resistance, which results in reducing survival benefits. Immunotherapy showed great promise in treating solid tumours; however, clinically significant improvements have not been demonstrated for patients with prostate cancer, highlighting specific drawbacks of this therapeutic modality. Hence, exploring novel strategies to synergistically enhance the efficacy of prostate cancer immunotherapy is imperative. Clinical investigations have focused on the combined use of targeted or gene therapy and immunotherapy for prostate cancer. Notably, tumour-specific antigens and inflammatory mediators are released from tumour cells after targeted or gene therapy, and the recruitment and infiltration of immune cells, including CD8+ T cells and natural killer cells activated by immunotherapy, are further augmented, markedly improving the efficacy and prognosis of prostate cancer. Thus, immunotherapy, targeted therapy and gene therapy could have reciprocal synergistic effects in prostate cancer in combination, resulting in a proposed synergistic model encompassing these three therapeutic modalities, presenting novel potential treatment strategies for prostate cancer.

Key points

  • Prostate cancer is generally considered to consist of an immunologically cold tumour with low immune-cell infiltration and low immunogenic response.

  • Immunotherapies for prostate cancer such as immune checkpoint blockade have limited antitumour activity, encouraging research into novel strategies to potentiate the efficacy of immunotherapy.

  • Targeted therapy is the mainstay treatment for patients with prostate cancer, but it sometimes fails to improve the clinical outcomes owing to drug resistance.

  • Gene therapy for prostate cancer demonstrates a generally good safety profile but limited efficacy, and so has potential for prostate cancer treatment, particularly in promoting the efficacy of immunotherapy.

  • A synergistic targeting model has been proposed focusing on potentiating the effect of immunotherapy through targeted or gene therapy. This model is a novel treatment strategy for overcoming drug resistance and immunosuppression for prostate cancer.

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Fig. 1: Mechanisms of the major immunotherapies for prostate cancer.
Fig. 2: Mechanisms of major drug target signalling pathways for prostate cancer and target drugs.
Fig. 3: The three major gene therapies for prostate cancer, including immunomodulatory, corrective and cytolytic gene therapies.
Fig. 4: Synergistic effect of targeted therapy for prostate cancer.
Fig. 5: Conceptual model of the synergistically enhanced effect of targeted combination therapy for prostate cancer.

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Acknowledgements

This study was supported by the National Key R&D Program of China (2023YFC3403200), the National Natural Science Foundation of China (82472774 and 81702536). We thank all the colleagues from the Department of Urology, Institute of Urology, West China Hospital, Sichuan University, for supporting our work.

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  1. These authors contributed equally: Xuanji Li, Zeyu Han.

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  1. Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China

    Xuanji Li, Zeyu Han & Jianzhong Ai

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  1. Xuanji Li
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  2. Zeyu Han
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Li, X., Han, Z. & Ai, J. Synergistic targeting strategies for prostate cancer. Nat Rev Urol 22, 645–671 (2025). https://doi.org/10.1038/s41585-025-01042-6

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