CD8+ T cell exhaustion is a stable dysfunctional state driven by chronic antigen stimulation in the tumor microenvironment (TME). Differentiation of exhausted CD8+ T cells (CD8+ TEXs) is accompanied by extensive transcriptional, epigenetic and metabolic reprogramming. CD8+ TEXs are mainly characterized by impaired proliferative and cytotoxic capacity as well as the increased expression of multiple co-inhibitory receptors. Preclinical tumor studies and clinical cohorts have demonstrated that T cell exhaustion is firmly associated with poor clinical outcomes in a variety of cancers. More importantly, CD8+ TEXs are regarded as the main responder to immune checkpoint blockade (ICB). However, to date, a large number of cancer patients have failed to achieve durable responses after ICB. Therefore, improving CD8+ TEXs may be a breakthrough point to reverse the current dilemma of cancer immunotherapy and eliminate cancers. Strategies to reinvigorate CD8+ TEXs in TME mainly include ICB, transcription factor-based therapy, epigenetic therapy, metabolism-based therapy and cytokine therapy, which target on different aspects of exhaustion progression. Each of them has its advantages and application scope. In this review, we mainly focus on the major advances of current strategies to reinvigorate CD8+ TEXs in TME. We summarize their efficacy and mechanisms, identify the promising monotherapy and combined therapy and propose suggestions to enhance the treatment efficacy to significantly boost anti-tumor immunity and achieve better clinical outcomes.

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