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Background <p>PD-L1 is a crucial immune checkpoint protein that limits the effectiveness of antitumor immunity. Blocking the PD-L1/PD-1 pathway has shown promise in cancer treatment, but low response rates to checkpoint inhibitors highlight the need for alternative therapeutic strategies. Metformin, a drug primarily used for diabetes, has gained attention as a potential cancer treatment due to its effects on PD-L1 expression, the tumor microenvironment, and its ability to inhibit the proliferation of tumor cells. Meta-analyses suggest that metformin may reduce the incidence and improve the prognosis of bladder cancer in patients with type 2 diabetes, but the exact mechanisms by which it exerts its effects remain unclear.</p> Materials <p>This study employed a syngeneic orthotopic bladder cancer model with immunocompetent C57BL/6 mice to evaluate metformin’s therapeutic effects. Safe dosage was established through a maximum tolerated dose (MTD) test, identifying 150&#xa0;mg/kg/day as suitable. Tumor size, body weight, survival, and PD-L1 expression were measured, while a tetrazolium-based assay assessed bladder cancer cell proliferation <i>in vitro</i>.</p> Results <p>Findings revealed elevated PD-L1 gene and protein expression in mouse bladder cancer tissues. <i>In vitro</i>, metformin inhibited PD-L1 expression and proliferation of MB49 mouse bladder cancer cells. <i>In vivo</i>, metformin reduced cancer cachexia, tumor size, and improved survival at 150&#xa0;mg/kg/day. Importantly, metformin attenuated tumor-induced PD-L1 upregulation in a dose-dependent manner.</p> Conclusion <p>Overall, this study suggests that bladder tumors can increase PD-L1 expression to promote PD-L1–mediated intrinsic tumor growth pathways, and metformin effectively downregulates PD-L1 expression, suppresses bladder cancer cell proliferation, and prolongs survival in an orthotopic bladder cancer mouse model.</p>

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Metformin as an anti-cancer agent against bladder cancer acts via PD-L1 downregulation in an orthotopic mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Chang-Ching Yeh,
  • Pei-Chu Tsai,
  • Yung-Deng Song,
  • Yong-Seng Low,
  • Chih-Hao Hsu,
  • Shiu-Ju Yang,
  • Yih-Yuan Chen,
  • Horng-Yunn Dou

摘要

Background

PD-L1 is a crucial immune checkpoint protein that limits the effectiveness of antitumor immunity. Blocking the PD-L1/PD-1 pathway has shown promise in cancer treatment, but low response rates to checkpoint inhibitors highlight the need for alternative therapeutic strategies. Metformin, a drug primarily used for diabetes, has gained attention as a potential cancer treatment due to its effects on PD-L1 expression, the tumor microenvironment, and its ability to inhibit the proliferation of tumor cells. Meta-analyses suggest that metformin may reduce the incidence and improve the prognosis of bladder cancer in patients with type 2 diabetes, but the exact mechanisms by which it exerts its effects remain unclear.

Materials

This study employed a syngeneic orthotopic bladder cancer model with immunocompetent C57BL/6 mice to evaluate metformin’s therapeutic effects. Safe dosage was established through a maximum tolerated dose (MTD) test, identifying 150 mg/kg/day as suitable. Tumor size, body weight, survival, and PD-L1 expression were measured, while a tetrazolium-based assay assessed bladder cancer cell proliferation in vitro.

Results

Findings revealed elevated PD-L1 gene and protein expression in mouse bladder cancer tissues. In vitro, metformin inhibited PD-L1 expression and proliferation of MB49 mouse bladder cancer cells. In vivo, metformin reduced cancer cachexia, tumor size, and improved survival at 150 mg/kg/day. Importantly, metformin attenuated tumor-induced PD-L1 upregulation in a dose-dependent manner.

Conclusion

Overall, this study suggests that bladder tumors can increase PD-L1 expression to promote PD-L1–mediated intrinsic tumor growth pathways, and metformin effectively downregulates PD-L1 expression, suppresses bladder cancer cell proliferation, and prolongs survival in an orthotopic bladder cancer mouse model.