T-cell exhaustion, initially identified in chronic infections, is a state of hypo-responsiveness in T cells, characterized by overexpression of inhibitory receptors, decreased production of effector cytokines, and impaired cytotoxic activity. This condition is prevalent in the tumor microenvironment (TME), leading to cancer immune evasion. PD-1 is the primary inhibitory receptor regulating T-cell exhaustion, and blocking its pathway has shown promising results in cancer immunotherapy. The review discusses the molecular mechanisms of T-cell exhaustion, including the role of inhibitory receptors, transcription factors, and cytokines, as well as the extrinsic factors contributing to T-cell dysfunction in the TME. Therapeutic interventions targeting inhibited receptors, such as CTLA-4 and PD-1/PD-L1 antibodies, have demonstrated significant clinical benefits in various cancers. However, challenges remain, including the need for more comprehensive understanding of inhibitory receptor functions and the development of combined therapies to enhance response rates. Overall, reversing T-cell exhaustion represents a promising strategy for cancer treatment.T-cell exhaustion, initially identified in chronic infections, is a state of hypo-responsiveness in T cells, characterized by overexpression of inhibitory receptors, decreased production of effector cytokines, and impaired cytotoxic activity. This condition is prevalent in the tumor microenvironment (TME), leading to cancer immune evasion. PD-1 is the primary inhibitory receptor regulating T-cell exhaustion, and blocking its pathway has shown promising results in cancer immunotherapy. The review discusses the molecular mechanisms of T-cell exhaustion, including the role of inhibitory receptors, transcription factors, and cytokines, as well as the extrinsic factors contributing to T-cell dysfunction in the TME. Therapeutic interventions targeting inhibited receptors, such as CTLA-4 and PD-1/PD-L1 antibodies, have demonstrated significant clinical benefits in various cancers. However, challenges remain, including the need for more comprehensive understanding of inhibitory receptor functions and the development of combined therapies to enhance response rates. Overall, reversing T-cell exhaustion represents a promising strategy for cancer treatment.