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Zoledronic acid enhances the antitumor efficacy of the PSMA CAR-T cells for bone tumors, but impedes the ability to control metastases of prostate cancer in mice

Cancer Gene Therapy (2026)Cite this article

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Abstract

The chimeric antigen receptor (CAR)-T cell therapy has shown promise for the treatment of hematological and solid tumors. Although CAR-T cells targeting PSMA showed robust antitumor efficacy for prostate cancer in preclinical studies, the clinical benefits of PSMA CAR-T cells are unsatisfactory. To maximize the efficacy of this immunotherapy, we combined zoledronic acid (ZOL), a first-line prophylactic drug against skeletal-related events (SREs) and for bone pain management in patients with advanced prostate cancer, with PSMA CAR-T cells for the treatment of prostate cancer. In mice with intratibial inoculation of 22Rv1 prostate tumor, ZOL treatment after PSMA CAR-T cells infusion inhibited growth of the primary intratibial tumor, while it increased the extraskeletal metastasis, demonstrating that ZOL impedes the long-term immunosurveillance, albeit it enhances the short-term antitumor capability of the CAR-T cells. Mechanistically, ZOL showed no increase in the frequency of γδT cell phenotype. Finally, we found that ZOL induced hyperactivation and eventually led to exhaustion of the PSMA CAR-T cells, elucidating the impediment clues of ZOL on the T cell therapy. Our study demonstrates the necessity to balance the contribution of ZOL when combined with CAR-T cell therapy for prostate cancer.

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Fig. 1: Characteristics of PSMA CAR-T cells.
Fig. 2: PSMA CAR-T cells shown robust PSMA-targeted cytotoxicity in vitro.
Fig. 3: ZOL promotes PSMA CAR-T cells in inhibiting intratibial prostate tumor growth.
Fig. 4: ZOL affects the efficacy of PSMA CAR-T cells against extraskeletal metastatic prostate tumors.
Fig. 5: ZOL treatment does not induce polarization of CAR-T cells toward a γδT cell phenotype in vitro and in vivo when IL-2 cytokine-deprived.
Fig. 6: ZOL impedes the long-term immunosurveillance of PSMA CAR-T cells.

Data availability

No new unique data were generated from this study. The data used in the manuscript are available from material and methods, and results.

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Acknowledgements

This study was supported by the National Key Research and Development Program (2025YFC3409800), Innovative Drug Research and Development National Science and Technology Major Project, Sichuan Science and Technology Program (2026NSFSC1902), the China Postdoctoral Science Foundation (2024M762205), Postdoctoral Fellowship Program of CPSF (GZC20250987), and Postdoctoral Research Fund of West China Hospital, Sichuan University (2025HXBH022).

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  1. Yong Huang

    Present address: Department of Laboratory Medicine, General Hospital of Western Theater Command of PLA, Chengdu, Sichuan, China

  2. These authors contributed equally: Dan Li, Xinyu Gu, Jing Li.

Authors and Affiliations

  1. Department of Biotherapy, the State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China

    Dan Li, Xinyu Gu, Jing Li, Yong Huang, Wei-Lin Zhou, Jiaqian Li, Fengling Wang, Feiyang Yan, Haozhan Gao, Xue Ying, Yikun Li, Shimao Qi & Wei Wang

  2. Department of Biotherapy, Cancer center, West China Hospital, Sichuan University, Chengdu, China

    Yueting Zhu & Jiyan Liu

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Contributions

WW, and JYL designed this study and supervised the whole investigation. DL, JL, XG, QS, and YH designed and performed experiments, analyzed the experimental data, and prepared the manuscript. FW, WZ, JQL, and YZ provided important technical support and performed some experiments. FY, XY, YL, and HG checked and verified the data reported in this manuscript. All authors participated in revising and approving this manuscript.

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Correspondence to Wei Wang.

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Li, D., Gu, X., Li, J. et al. Zoledronic acid enhances the antitumor efficacy of the PSMA CAR-T cells for bone tumors, but impedes the ability to control metastases of prostate cancer in mice. Cancer Gene Ther (2026). https://doi.org/10.1038/s41417-026-01025-8

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