Metabolic modulation of CD8⁺ T cells by metformin: A promising adjuvant strategy for CD8⁺ T Cell-Based Immunotherapies

CD8⁺ T cells play a pivotal role in immune defense through their cytotoxic activity. However, persistent antigen exposure and immunosuppressive microenvironments drive CD8⁺ T cells into a dysfunctional or exhausted state, thereby limiting the effectiveness of CD8⁺ T cell-based immunotherapies. Increasing evidence indicates that CD8 + T cell activation and effector functions are tightly coupled to dynamic metabolic reprogramming that sustains the energetic and biosynthetic requirements for effective immune responses. Metformin, beyond its established role as an antidiabetic medication, demonstrates considerable promise as an immune-metabolic adjuvant capable of enhancing the efficacy of CD8⁺ T cell-based immunotherapies and reshaping immune responses across various pathological conditions. In this review, we provide a comprehensive overview of the current insights into the metabolic and functional regulation of CD8⁺ T cells by metformin in a context-dependent manner, with an emphasis on its therapeutic potential as an immunotherapeutic adjuvant. We also highlight the translational opportunities and challenges associated with the clinical integration of metformin and propose strategies to overcome context-specific barriers to its clinical application. • Metabolic regulation is a key determinant of CD8⁺ T cell fate and function • Metformin functions as a disease-context-specific immunometabolic modulator • Metformin enhances CD8⁺ T cell-based therapies across diverse disease settings