Liver immune tolerance and regulated cell death in transplantation and hepatocellular carcinoma: shared mechanisms, divergent outcomes

The liver constantly encounters gut-derived antigens, microbial molecules, and food antigens. This environment has shaped a tissue-specific tolerance network centered on tolerogenic antigen presentation, immune-checkpoint activation, regulatory cell expansion, and metabolic suppression. This feature protects the liver during prolonged inflammation and gives it an immunological identity that most solid organs lack. Regulated cell death (RCD) and dead-cell clearance form a critical mechanistic layer within this network. Efficient efferocytosis of apoptotic cells reinforces resolution and tolerance, whereas necroptosis, pyroptosis, and ferroptosis disrupt cell membranes and release danger signals that reshape myeloid activation, T-cell function, and the tumor microenvironment. In liver transplantation, this tolerogenic tendency produces donor-specific hyporesponsiveness, allowing a selected subset of stable recipients to stop immunosuppression while maintaining graft function—a state called operational tolerance. In hepatocellular carcinoma (HCC), tumors exploit the same immunosuppressive axes to block anti-tumor T-cell infiltration and effector function. Anti-PD-L1 therapy combined with anti-angiogenic treatment improves survival, demonstrating that partial disruption of tumor immunosuppression is therapeutically effective. Spatial transcriptomics and single-cell sequencing reveal that SPP1-positive macrophages and cancer-associated fibroblasts form a tumor immune barrier that excludes lymphocytes, showing that hepatic tolerance is organized in space. This duality becomes most dangerous in HCC recurrence after liver transplantation, where immune checkpoint inhibitors boost anti-tumor immunity but also raise the risk of acute rejection, graft failure, and death. Unlike reviews focused on hepatic immune tolerance, regulated cell death, or HCC immunobiology in isolation, this review integrates these processes across the physiological liver, transplantation, HCC, and post-transplant recurrence. We define this coordinated hyporesponsive state as the liver immune tolerance program (ITP), generated by cellular, molecular, spatial, metabolic, and cell-death-related networks. Rather than treating these processes separately, we position RCD and dead-cell clearance as a “death-to-immunity axis,” systematically compare ITP remodeling in the physiological liver, transplantation, and HCC, and use post-transplant HCC recurrence as a clinical crossover setting in which graft protection and antitumor immune surveillance become therapeutic considerations. On this basis, we propose precision immune homeostasis: rather than choosing between immunosuppression and immune activation, immune status should be adjusted to an individualized range that protects the graft while preserving anti-tumor immune surveillance.