CD8+ T Cell Exhaustion and Tumor Immune Checkpoint Blockade: Mechanisms, Heterogeneity, and Combination Intervention Strategies
DOI:
https://doi.org/10.71204/dkzdp879Keywords:
CD8+ T Cells, T Cell Exhaustion, Immune Checkpoint Blockade, Tumor Microenvironment, ImmunotherapyAbstract
CD8+ T cells are the core effector cells in anti-tumor immunity, but under continuous tumor antigen stimulation and inhibitory microenvironment, they gradually enter a state of dysfunction, showing reduced effector secretion, decreased proliferation, persistent expression of inhibitory receptors, and abnormal metabolic adaptation, which are driven by a unified transcriptional, epigenetic, metabolic, and microenvironmental exhaustion program. T cell exhaustion is a major reason why immune checkpoint blockade (ICB) therapy has limited effectiveness and also a key target for combination treatment strategies. In recent years, single-cell sequencing, spatial transcriptomics, and functional immunology studies have shown that exhausted T cells are not a single state-they include heterogeneous subgroups such as progenitor exhausted T cells (Tpex), intermediate exhausted T cells, and terminal exhausted T cells. Blocking PD-1/PD-L1 and CTLA-4 can partly restore T cell function, but primary and secondary resistance are still common. This article reviews the unified mechanisms of CD8+ T cell exhaustion and, organized around the axis of 'mechanism–heterogeneity–ICB response–combination strategies', explores potential strategies for immune checkpoint blockade related to CD8+ T cell exhaustion, and also discusses biomarkers and future research directions.
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