Mitochondrial Regulation of CD8⁺ T Cells: Mechanisms and Therapeutic Modulation

Abstract Mitochondria are integral to the regulation of CD8 + T cell function, critically influencing processes such as activation, differentiation, and long‐term persistence during immune responses. Emerging evidence highlights the detrimental impact of mitochondrial dysfunction on CD8 + T cell activity, contributing to immune exhaustion and impairing both antitumor and antiviral immunity. This underscores the importance of understanding and modulating mitochondrial dynamics to optimize T cell‐based immunotherapies. In this review, a comprehensive and in‐depth analysis of the essential mitochondrial processes—including biogenesis, redox homeostasis, and metabolic reprogramming is provided—that govern CD8 + T cell function and are intricately linked to their therapeutic potential. The current strategies aimed at enhancing mitochondrial function in CD8 + T cells are also examined, focusing on both metabolic reprogramming and mitochondrial‐targeted interventions. Despite these promising approaches, several significant challenges remain, such as achieving selective targeting, addressing mitochondrial plasticity, and mitigating off‐target effects. Overcoming these obstacles will be crucial to improving the clinical efficacy and safety of mitochondrial modulation therapies. As the understanding of mitochondrial dynamics within CD8 + T cells continues to evolve, there is growing potential to leverage these insights to improve immune‐based therapies across a range of diseases, including cancer and viral infections.