Mitochondrial dysfunction in T‑cell exhaustion: Its contribution to the efficacy of cancer immunotherapy (Review)

Mitochondria play a pivotal role in the regulation of T‑cell function, particularly in the context of T‑cell exhaustion within the tumor microenvironment. T‑cell exhaustion, characterized by impaired effector functions and the sustained expression of inhibitory receptors, poses a significant barrier to effective antitumor immunity and limits the success of immunotherapies. Emerging evidence indicates that mitochondrial dysfunction is a contributor to the metabolic and functional decline of tumor‑infiltrating lymphocytes. The present review critically synthesizes the available mechanistic and translational literature on mitochondrial dysfunction in T‑cell exhaustion, with particular attention paid to mitochondrial dynamics, mitophagy, and the threshold‑dependent duality of mitochondrial reactive oxygen species. The evidence is organized not by pathway alone, but by intervention class and level of evidence, so that the strategies with demonstrated clinical traction can be distinguished from those that remain at the proof‑of‑concept stage. Of note, four intervention classes are discussed: Metabolic reprogramming, enhancement of mitochondrial biogenesis, redox‑directed modulation and intercellular mitochondrial transfer, together with mitochondria‑directed pharmacological and nanoscale delivery platforms. Clinical translation is assessed against trials registered on ClinicalTrials.gov, of which the most advanced evaluate metformin in combination with immune checkpoint inhibitors. Mitochondrial dysfunction is also placed in the context of other established drivers of exhaustion, the limitations of the available evidence are stated, and the specific questions that need to be answered before mitochondrial targeting can be incorporated into immunotherapy regimens are also stated. Rather than claiming that mitochondrial dysfunction is a single dominant constraint, it is argued herein that its therapeutic value lies in being a mechanistically tractable and pharmacologically accessible component of a multifactorial resistance program.