THE ROLE AND THERAPEUTIC STRATEGIES OF PRECURSOR EXHAUSTED CD8-positive T CELLS IN TUMOR IMMUNITY
Keywords:
CD8-positive T cells, Precursor exhausted T cells, Tumor immunity, Immune checkpoint inhibitorsAbstract
The clinical use of immune checkpoint inhibitors (ICIs) has markedly improved outcomes in a range of malignancies. Even so, overall response rates remain unsatisfactory, and acquired resistance often erodes durable clinical benefit. Accumulating evidence suggests that terminally exhausted CD8-positive T cells are not the principal population that expands after checkpoint blockade. Rather, precursor exhausted CD8-positive T cells (Tpex), which retain self-renewal capacity and the potential to redifferentiate, provide the main cellular foundation for sustained antitumor immunity. In most settings, Tpex are characterized by high TCF1 expression, relatively low levels of terminal exhaustion markers, and responsiveness to PD-1 blockade. Their generation and persistence are shaped by several interconnected factors, including tumor-draining lymph nodes, intratumoral antigen-presenting cell niches, transcription factor circuits, metabolic adaptation, and epigenetic remodeling. Research on Tpex is now reshaping the conceptual basis of cancer immunotherapy. The emphasis is shifting away from simply amplifying immune activation and toward expanding the precursor pool, preserving cellular plasticity, and modulating the timing of differentiation. This review outlines the conceptual definition, biological basis, fate-regulatory mechanisms, and translational significance of Tpex in tumor immunotherapy. It also discusses current challenges, such as the absence of a unified phenotypic definition, the shortage of longitudinal causal evidence, and the still-limited body of clinical translational data. Overall, this review aims to provide a useful framework for refining precision immunotherapeutic strategies.References
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