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 prog...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.展开更多
基金supported by Chinese National Natural Science Funds(32125016,32525002,U24A20371,and W2411011)a special program from the Ministry of Science and Technology of China(2021YFA1101000,2022YFA1105200,2022YFF0608400,and 2023YFA1800200,2024YFC2707400)+6 种基金a Key R&D Program of Zhejiang Province(2023C03044 and 2024C03142)the Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022505,ZXL2022442)the Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027,YXY2302017)the Joint Proiect of Pinnacle Disciplinary Group,the Second Affiliated Hospital of Chongqing Medical,Bo Xi Clinical Research Project of the First Affiliated Hospital of Soochow University(BXLC007)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Zhejiang Provincial Natural Science Foundation of China(LMS25H050002)the National Traditional Chinese Medicine Comprehensive Reform Demonstration Zone Science and Technology Construction Project(GZY-KJS-ZJ-2025-092).
文摘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.
