ECM2026, 14-17 June 2026, Copenhagen, DenmarkScott L. Friedman, Professor, Dean for Therapeutic Discovery and Chief of the Division of Liver Diseases, Icahn School of Medicine, Mount Sinai, New York.
Abstract: Fibrosis is a maladaptive wound-healing response driven by persistent activation of fibroblasts and, in the liver, hepatic stellate cells (HSCs), resulting in extracellular matrix (ECM) accumulation, architectural distortion, and organ failure. Emerging cellular therapeutics—particularly chimeric antigen receptor (CAR)–engineered immune cells—are redefining antifibrotic strategies by enabling selective targeting of pathogenic stromal populations while aiming to preserve tissue homeostasis.
In liver, activated HSCs represent a rational therapeutic target, yet their heterogeneity and homeostatic roles necessitate precision approaches. Single-cell analyses have identified senescent HSC subsets that promote inflammation and carcinogenesis. Similarly, fibroblast activation protein (FAP), expressed on subsets of fibrogenic cells across organs, has emerged as a shared stromal target. FAP-directed CAR T cells attenuate cardiac fibrosis as well as hepatic fibrosis, where activated HSCs express FAP.
However, depletion of homeostatic fibroblasts should be avoided. In liver, complete HSC depletion impairs liver regeneration, underscoring the physiological role of some HSCs in tissue regeneration. To mitigate risks associated with long-term CAR persistence—undesirable in non-malignant disease—transient in vivo CAR expression via lipid nanoparticle (LNP)–delivered mRNA enables dose-titrated, self-limited antifibrotic activity. This approach avoids durable genomic integration and may enhance safety. Extending beyond liver, FAP-targeted CAR-T strategies display anti-fibrotic activity in other settings (e.g., dystrophic muscle fibrosis), supporting the concept that shared stromal antigens can be leveraged across organs while still requiring careful, context-specific validation.
Beyond cytotoxic depletion, CAR regulatory T cells (CAR Tregs) offer an immunomodulatory paradigm by restoring local tolerance and dampening inflammatory circuits that perpetuate fibrosis. Engineering advances—including optimized costimulatory domains (CD28 vs 4-1BB), HLA-independent TCR fusion constructs, logical gating strategies, and exhaustion-resistant transcriptional programming—seek to enhance specificity, persistence, and function within the immunosuppressive, ECM-rich fibrotic microenvironment.
Major translational barriers remain. In liver, fibrotic capillarization of liver sinusoidal endothelial cells and dense ECM impede T-cell access, while local immunoregulatory networks (Tregs, myeloid-derived suppressor cells, PD-1/PD-L1 signaling, and metabolic enzymes such as IDO and arginase) restrict effector activity. Additionally, conventional lymphodepletion may be inappropriate in chronic liver disease.
Key prospects—and hurdles—include improving antigen specificity to avoid on-target/off-tissue toxicity, exploiting transient CAR expression (mRNA/LNP) to enhance safety, and integrating single-cell/spatial biomarkers with imaging/genetic risk to select patients, time intervention, and monitor response. Collectively, the field is moving from broad antifibrotic signaling blockade toward precision cellular therapeutics that target defined pathogenic cell states and re-establish durable tissue repair.
Collectively, cellular therapeutics are moving beyond oncology toward precision antifibrotic interventions. Future progress will depend on refined target selection, controllable persistence, and integration of stromal, immune, and metabolic insights to achieve durable fibrosis reversal while preserving regenerative capacity.
