FAP CAR-T Therapy Emerges as a Novel Antifibrotic Strategy in Liver Disease : JHEP Report | May 2026

Introduction

Chimeric antigen receptor T-cell therapy has revolutionized hematologic oncology and is increasingly being explored beyond cancer. In chronic liver disease, progressive fibrosis driven by activated hepatic stellate cells (HSCs) remains a central pathogenic mechanism leading to cirrhosis and hepatocellular carcinoma (HCC). Effective therapies capable of selectively targeting pathogenic fibrogenic cells are urgently needed.

Problem Statement

Current antifibrotic therapies remain limited and largely ineffective in advanced fibrosis or cirrhosis. Because hepatic stellate cells are heterogeneous and also contribute to normal hepatic homeostasis, nonspecific depletion strategies may produce harmful consequences. Selective targeting of activated fibrogenic HSC populations has therefore emerged as a major therapeutic challenge.

Summary

This editorial highlights a major translational advance demonstrating the therapeutic potential of fibroblast activation protein (FAP)-targeted CAR-T cells in liver fibrosis and hepatocellular carcinoma. Activated HSCs were shown to highly express FAP, whereas quiescent HSCs and most normal tissues demonstrated minimal expression, making FAP an attractive selective target for cellular immunotherapy. In multiple murine fibrosis models—including toxic, cholestatic, metabolic and alcohol-associated liver injury—single-dose anti-FAP CAR-T therapy markedly reduced fibrosis severity, collagen deposition, α-smooth muscle actin expression and fibrogenic gene programs. The antifibrotic effects exceeded those observed with pharmacologic FAP inhibition, emphasizing the potency of immune-mediated cellular depletion. Mechanistic analyses using single-cell and transcriptomic approaches demonstrated reduction of activated HSC populations, suppression of extracellular matrix pathways and enhanced hepatic infiltration of activated T cells and NK cells. Macrophage subsets with phagocytic signatures contributed to clearance of apoptotic activated HSCs, indicating coordinated immune remodeling within the fibrotic liver microenvironment. Importantly, anti-FAP CAR-T cells retained efficacy even in advanced cirrhotic models, suggesting that engineered T cells can successfully penetrate dense fibrotic tissue. The approach also demonstrated antitumor activity in experimental HCC, reducing tumour burden, AFP levels, epithelial–mesenchymal transition and cancer stemness signatures while promoting cytotoxic immune activation. The article further discusses broader implications of stromal-targeted immunotherapy, particularly in desmoplastic malignancies such as pancreatic, colorectal and breast cancer, where FAP-expressing fibroblasts contribute to immune exclusion and tumor progression. Collectively, these findings position FAP CAR-T therapy as a highly promising platform strategy capable of simultaneously remodeling fibrosis, restoring immune surveillance and potentially preventing fibrosis-associated carcinogenesis.