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

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.