Cell Therapy in Advanced Cirrhosis: From Preclinical Evidence to Clinical Application.

End-stage liver disease (ESLD) presents a significant worldwide health and economic burden accounting for 4% of global deaths. When ESLD develops into liver failure, the only effective treatment is liver transplantation, which is limited by surgical and access barriers and significant posttransplant complications. Furthermore, the scarcity of suitable donors means many patients deteriorate or die while waiting for a transplant, highlighting the need for alternative therapeutic strategies. ESLD is characterized by a multifactorial pathophysiology driven by a complex interplay of extensive parenchymal damage, self-perpetuating chronic inflammation, and advanced fibrosis. Cell-based therapies have emerged as promising alternatives to restore liver function through either parenchymal replacement or microenvironment remodeling. While primary hepatocyte transplantation remains the benchmark for parenchymal replacement, emerging modalities have undergone substantial evolution, demonstrating an enhancement in the integration of the transplanted cells into the diseased liver tissue to ameliorate liver function. Despite these advances, suboptimal engraftment due to the negative effect of the liver dysfunctional microenvironment results in limited durability and functional impact of parenchymal replacement. As the negative role of the dysfunctional microenvironment in disease progression became clearer, the focus for disease-modifying cell therapy shifted toward microenvironment-remodeling therapies. Mesenchymal stromal cells, regulatory T cells, chimeric antigen receptor T cells, and regenerative macrophages have been recognized as powerful modalities, with the potential to offer durable restoration of liver function by exerting anti-inflammatory and antifibrotic effects, thereby favoring endogenous repair. In this review, we discuss these evolving platforms, delineate their mechanistic underpinnings, and define the opportunities and challenges that shape their translation into clinically viable alternatives for treating ESLD.