• Kupffer cells (KCs) are primary mediators of early immune rejection of transplanted allogeneic hepatic progenitors (allo-HPs) in an injured liver, leading to their elimination within 24 hours.
• Selective depletion of KCs delays monocyte recruitment and significantly improves the survival, homing, and repopulation of allo-HPs in a sustained inflammatory liver niche.
• The study provides a mechanistic insight into innate immune barriers, particularly KC-mediated clearance, that currently limit the efficacy of allogeneic hepatocyte transplantation.
• KC ablation represents a promising strategy to enhance engraftment and therapeutic outcomes of cell-based therapies for liver defects, potentially reducing reliance on systemic immunosuppression.