A pathogenic CD8⁺ TRM-chemokine axis orchestrates liver fibrosis and provides circulating biomarkers during chronic Clonorchis sinensis infection.

Chronic liver fluke infections represent a major global health burden, driving liver fibrosis and elevating cancer risk, yet the immunological mechanisms linking persistent infection to tissue damage remain poorly defined. Using Clonorchis sinensis, a carcinogenic liver fluke infecting millions worldwide, as a representative model, we map immune responses during chronic infection in mice. We show that intrahepatic CD8⁺ tissue-resident memory T cells (TRM) progressively accumulate and drive pathology by producing chemokines that promote immune recruitment and fibroblast activation. Depletion of CD8⁺ T cells during defined disease phases markedly alleviates liver inflammation and fibrosis, demonstrating their causal role. Strikingly, C-C motif chemokine ligand 4, predominantly secreted by CD8⁺ TRM cells, correlates with fibrosis severity in both experimental models and patient cohorts, establishing it as a circulating biomarker for noninvasive disease monitoring. These findings define a pathogenic CD8⁺ TRM-chemokine axis underlying helminth-induced liver injury and highlight TRM-derived chemokines as biomarkers and therapeutic targets for fibrosis across chronic parasitic infections.