T-cell exhaustion is a state of dysfunction in T cells within the tumor microenvironment (TME), characterized by increased inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3, LAG-3, BTLA, TIGIT), reduced effector functions, and impaired cytotoxicity. This dysfunction prevents effective cancer elimination and is a major barrier to immune therapy. Restoring exhausted T cells is a promising strategy for cancer treatment, with significant clinical progress in recent years. This review summarizes the current understanding of T-cell exhaustion in cancer, its regulatory mechanisms, and therapeutic interventions targeting exhausted T cells in clinical trials. T-cell exhaustion is primarily driven by chronic antigen exposure and the immunosuppressive TME, which includes cancer cells, inflammatory cells, stromal cells, and cytokines. The TME promotes the terminal differentiation of T cells into exhausted states, characterized by the loss of effector functions and increased expression of inhibitory receptors. PD-1 is the most studied inhibitory receptor, and its blockade has shown promising results in restoring T-cell function and improving anti-tumor responses. Other inhibitory receptors, such as CTLA-4, TIM-3, LAG-3, BTLA, and TIGIT, also play critical roles in T-cell exhaustion, and their combined blockade may enhance therapeutic efficacy. Extrinsic factors, including regulatory T cells (Tregs), dendritic cells (DCs), macrophages, and myeloid-derived suppressor cells (MDSCs), contribute to T-cell exhaustion by secreting immunosuppressive cytokines like IL-10 and TGF-β, and by promoting the expression of inhibitory receptors on T cells. These factors create a suppressive environment that limits T-cell activation and function. Therapeutic interventions targeting T-cell exhaustion include checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, which have shown significant clinical benefits in various cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. Combination therapies, such as the simultaneous blockade of multiple inhibitory receptors, have also demonstrated improved outcomes in clinical trials. Despite these advances, challenges remain, including the need to understand the distinct roles of different inhibitory receptors, the potential for excessive T-cell activation and toxicity, and the need for more effective combination therapies. Further research is needed to fully understand the mechanisms of T-cell exhaustion and to develop more targeted and effective treatments for cancer.T-cell exhaustion is a state of dysfunction in T cells within the tumor microenvironment (TME), characterized by increased inhibitory receptors (e.g., PD-1, CTLA-4, TIM-3, LAG-3, BTLA, TIGIT), reduced effector functions, and impaired cytotoxicity. This dysfunction prevents effective cancer elimination and is a major barrier to immune therapy. Restoring exhausted T cells is a promising strategy for cancer treatment, with significant clinical progress in recent years. This review summarizes the current understanding of T-cell exhaustion in cancer, its regulatory mechanisms, and therapeutic interventions targeting exhausted T cells in clinical trials. T-cell exhaustion is primarily driven by chronic antigen exposure and the immunosuppressive TME, which includes cancer cells, inflammatory cells, stromal cells, and cytokines. The TME promotes the terminal differentiation of T cells into exhausted states, characterized by the loss of effector functions and increased expression of inhibitory receptors. PD-1 is the most studied inhibitory receptor, and its blockade has shown promising results in restoring T-cell function and improving anti-tumor responses. Other inhibitory receptors, such as CTLA-4, TIM-3, LAG-3, BTLA, and TIGIT, also play critical roles in T-cell exhaustion, and their combined blockade may enhance therapeutic efficacy. Extrinsic factors, including regulatory T cells (Tregs), dendritic cells (DCs), macrophages, and myeloid-derived suppressor cells (MDSCs), contribute to T-cell exhaustion by secreting immunosuppressive cytokines like IL-10 and TGF-β, and by promoting the expression of inhibitory receptors on T cells. These factors create a suppressive environment that limits T-cell activation and function. Therapeutic interventions targeting T-cell exhaustion include checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies, which have shown significant clinical benefits in various cancers, including melanoma, non-small cell lung cancer, and renal cell carcinoma. Combination therapies, such as the simultaneous blockade of multiple inhibitory receptors, have also demonstrated improved outcomes in clinical trials. Despite these advances, challenges remain, including the need to understand the distinct roles of different inhibitory receptors, the potential for excessive T-cell activation and toxicity, and the need for more effective combination therapies. Further research is needed to fully understand the mechanisms of T-cell exhaustion and to develop more targeted and effective treatments for cancer.