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<p>Targeted radioligand therapy (TRT) is an emerging therapeutic modality for advanced tumors like metastatic castration-resistant prostate cancer. The patients bare, however, varying degrees of resistance to TRT, which would greatly lessen the treatment efficacy and response rate. Here, we find that oral medication of D-mannose effectively enhances the radiosensitivity of PSMA-positive murine RM1-hPSMA prostate cancer cells to TRT by suppressing glucose metabolism. This metabolic disruption not only impeded the proliferation of RM1-hPSMA cells but also augmented DNA damage within tumor cells subjected to TRT, co-promoting cell apoptosis. Interestingly, TRT-D-mannose combination strongly boosted the anti-tumor immune responses by inducing immunogenic cell death, disrupting the immune evasion mechanisms employed by tumor cells, and reducing immunosuppressive cells in the tumor. D-mannose significantly improved the TRT efficacy for highly aggressive murine RM1-hPSMA and human LNCaP Clone FGC models, without causing adverse effects. Hence, D-mannose is potentially a safe radio-sensitizer and a potent immune activator for TRT.</p> Graphical Abstract <p>D-mannose potentiates targeted radioligand therapy and immunotherapy of murine prostate tumor by suppressing glucose metabolism, increasing DNA damage, intensifying the immunogenic cell death, and impairing tumor immune escape.</p> <p></p>

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D-mannose augments targeted radioligand-immunotherapy of prostate cancer by enhancing radiosensitivity and reshaping immune microenvironment

  • 期刊论文

  • 发表日期：

    2025年6月14日

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  • Lei Tao,
  • Bin Xu,
  • Juan Sun,
  • Jiangtao Yang,
  • Fenghua Meng,
  • Zhiyuan Zhong

摘要

Targeted radioligand therapy (TRT) is an emerging therapeutic modality for advanced tumors like metastatic castration-resistant prostate cancer. The patients bare, however, varying degrees of resistance to TRT, which would greatly lessen the treatment efficacy and response rate. Here, we find that oral medication of D-mannose effectively enhances the radiosensitivity of PSMA-positive murine RM1-hPSMA prostate cancer cells to TRT by suppressing glucose metabolism. This metabolic disruption not only impeded the proliferation of RM1-hPSMA cells but also augmented DNA damage within tumor cells subjected to TRT, co-promoting cell apoptosis. Interestingly, TRT-D-mannose combination strongly boosted the anti-tumor immune responses by inducing immunogenic cell death, disrupting the immune evasion mechanisms employed by tumor cells, and reducing immunosuppressive cells in the tumor. D-mannose significantly improved the TRT efficacy for highly aggressive murine RM1-hPSMA and human LNCaP Clone FGC models, without causing adverse effects. Hence, D-mannose is potentially a safe radio-sensitizer and a potent immune activator for TRT.

Graphical Abstract

D-mannose potentiates targeted radioligand therapy and immunotherapy of murine prostate tumor by suppressing glucose metabolism, increasing DNA damage, intensifying the immunogenic cell death, and impairing tumor immune escape.