Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion

Abstract T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcriptional reprogramming, contribute to T cell dysfunction. Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity. These therapeutic strategies include immune checkpoint inhibition, cytokine therapies, metabolic reprogramming, and cell-based therapies. Despite these advancements, reversing T cell exhaustion presents several challenges, such as individual variability, resistance, and potential side effects. Furthermore, accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas. This review provides an overview of the history and milestones in T cell exhaustion research; summarizes the mechanisms of T cell exhaustion and its implications in cancer, chronic infections, and autoimmune diseases; discusses advancements and challenges in emerging therapies; and explores future research directions aimed at improving T cell function and enhancing immune responses.