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<p>Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering <i>γδ</i> T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance <i>γδ</i> T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of <i>γδ</i> T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in <i>γδ</i> T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored <i>γδ</i> T cell function. Clinical data further showed that high AMPK activity and increased <i>γδ</i> T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in <i>γδ</i> T cell-based immunotherapy for TNBC.</p>

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Metformin drives HIF-1α–mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Xuping Qin,
  • Haowen Zhong,
  • Meize Liu,
  • Tiantian Yu,
  • Rong Ma,
  • Ying Zhou,
  • Jingyu Chen,
  • Fen Liu,
  • Xiwei Wang,
  • Jianting Long

摘要

Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance γδ T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of γδ T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in γδ T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored γδ T cell function. Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.