Yu, Yi-RuImrichova, HanaWang, HaipingChao, TungXiao, ZhengtaoGao, MinRincon-Restrepo, MarcelaFranco, FabienGenolet, RaphaelCheng, Wan-ChenJandus, CamillaCoukos, GeorgeJiang, Yi-FanLocasale, Jason W.Zippelius, AlfredLiu, Pu-SteTang, LiBock, ChristophVannini, NicolaHo, Ping-Chih2020-10-212020-10-212020-10-212020-10-0510.1038/s41590-020-0793-3https://infoscience.epfl.ch/handle/20.500.14299/172650WOS:000575347200002Ho and colleagues report that mitochondrial dysfunction and impaired mitophagy triggered by the tumor microenvironment lead to subsequent epigenetic changes and cause permanent T cell exhaustion and dysfunction. The metabolic challenges present in tumors attenuate the metabolic fitness and antitumor activity of tumor-infiltrating T lymphocytes (TILs). However, it remains unclear whether persistent metabolic insufficiency can imprint permanent T cell dysfunction. We found that TILs accumulated depolarized mitochondria as a result of decreased mitophagy activity and displayed functional, transcriptomic and epigenetic characteristics of terminally exhausted T cells. Mechanistically, reduced mitochondrial fitness in TILs was induced by the coordination of T cell receptor stimulation, microenvironmental stressors and PD-1 signaling. Enforced accumulation of depolarized mitochondria with pharmacological inhibitors induced epigenetic reprogramming toward terminal exhaustion, indicating that mitochondrial deregulation caused T cell exhaustion. Furthermore, supplementation with nicotinamide riboside enhanced T cell mitochondrial fitness and improved responsiveness to anti-PD-1 treatment. Together, our results reveal insights into how mitochondrial dynamics and quality orchestrate T cell antitumor responses and commitment to the exhaustion program.Immunologyinhibitory receptor pd-1set enrichment analysistumor microenvironmentrna-seqcheckpointdysfunctiondifferentiationexpressionmitophagyalignmenttext::journal::journal article::research article