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IntroductionT cell functions are altered during chronic viral infections and tumor development. This is mainly manifested by significant changes in T cells' epigenetic and metabolic landscapes, pushing them into an 'exhausted' state. Reversing this T cell exhaustion has been emerging as a 'game-changing' therapeutic approach against cancer and chronic viral infection.Areas coveredThis review discusses the cellular pathways related to T cell exhaustion, and the clinical development and possible cellular targets that can be exploited thera