Cellular and molecular networks governing precursor exhausted CD8+ T cells in chronic liver disease: Implications for immunotherapy.

Chronic liver diseases of diverse etiologies, along with primary liver cancers, represent major global health burdens with limited curative options. CD8+ T-cell exhaustion is a central barrier to effective immune control in these pathological settings. However, precursor exhausted CD8+ T cells (Tpex), a stem-like subset with self-renewal and proliferative potential, retain the ability to generate effector-like progeny and sustain long-term immune surveillance. In this review, we first provide a definition of Tpex to distinguish them from other related CD8+ T-cell states, including terminally exhausted, effector-like exhausted, tissue-resident memory, and conventional memory T cells, in chronic liver diseases and liver cancer. We then summarize current knowledge on the fundamental biology, etiological dynamics, and therapeutic relevance of Tpex in both benign and malignant liver diseases. Specifically, we examine the transcriptional, metabolic, and microenvironmental networks that govern Tpex fate, with particular emphasis on how distinct etiologies, including viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and autoimmune hepatitis, differentially shape Tpex abundance and functional state. In chronic viral hepatitis, Tpex dynamics are critically influenced by viral persistence, metabolic context, and co-infections, which in turn have direct implications for the responsiveness to immune checkpoint blockade. In hepatocellular carcinoma and intrahepatic cholangiocarcinoma, Tpex signatures are not only correlated with clinical outcomes but also modulated by tumor genetic landscapes and the composition of the immune microenvironment. Finally, we highlight emerging Tpex-targeted therapeutic strategies, including co-stimulatory agonists, metabolic reprogramming, vaccines, CAR-T cell engineering, and gut microbiota modulation, as promising avenues to overcome immunotherapy resistance.