Abstract Chronic viral infections and cancer challenge immune control by enforcing sustained antigen exposure, which profoundly alters the fate and function of CD8 + T cells. In contrast to acute infections, which induce robust effector differentiation and durable immune memory, persistent infections and tumors drive CD8 + T cells into distinct states of functional adaptation. The best studied chronic adaptation is T cell exhaustion, which is characterized by impaired effector functions, reduced proliferative capacity, sustained expression of inhibitory receptors, and stable transcriptional and epigenetic reprogramming. T cell exhaustion is not a uniform or terminal condition but comprises heterogeneous and dynamic cellular states, including stem-like/precursor populations that retain self-renewal capacity and therapeutic responsiveness. These insights have reshaped our understanding of immune regulation in chronic disease and underpin the success of immune checkpoint blockade therapies. However, heterogeneous and often transient clinical responses highlight critical gaps in our mechanistic understanding of exhausted T cell biology. This review synthesizes recent advances in the cellular and molecular profiling of chronically stimulated CD8 + T cells across chronic viral infection and cancer, focusing on regulatory networks, defining factors, and tissue-specific cues that govern functional adaptation and exploring emerging therapeutic reprogramming strategies.
Luxenburger et al. (Mon,) studied this question.