Broken Engines of Immunity: Mitochondrial Dysfunction in T Cells Across Cancer and Complex Pathologies

ABSTRACT

Mitochondria have traditionally been viewed as the cellular ‘powerhouses’ responsible for energy production; however, they also play essential roles in a wide range of cellular processes, including macromolecule biosynthesis and the regulation of apoptosis. Accumulating evidence highlights their importance in immune regulation, particularly through their influence on T cell activation, proliferation, and effector function. In addition to ATP generation, mitochondria regulate redox and calcium homeostasis and produce metabolites that modulate the transcriptional and epigenetic programs of immune cells. Upon antigen recognition, T lymphocytes undergo marked metabolic reprogramming, characterised by increased glycolysis while preserving mitochondrial metabolism as a critical pathway. Mitochondrial dysfunction disrupts intracellular signalling and contributes to T cell exhaustion in diverse pathological contexts, including cancer and chronic viral infections. Consequently, strategies aimed at restoring mitochondrial function are emerging as promising therapeutic approaches to correct immune dysfunction driven by impaired T cell responses. Importantly, these alterations should not be interpreted solely as downstream consequences of chronic immune stimulation; rather, mitochondrial dysfunction can actively determine T‐cell fate, stabilise exhaustion‐associated programs, and define the extent to which dysfunctional T cells remain therapeutically reversible. This review first outlines mitochondrial structure, bioenergetics, dynamics, and quality‐control pathways and then examines how these processes are remodelled across naïve, effector, circulating‐memory, tissue‐resident‐memory, and exhausted T‐cell states. It subsequently integrates evidence from cancer, chronic viral infection, and ageing and evaluates mitochondria‐directed strategies for restoring T‐cell function.