Without stringent criteria, liver transplantation for hepatocellular carcinoma (HCC) can lead to high cancer recurrence and poor prognosis in the current treatment context. Checkpoint inhibitors can lead to long survival by targeting coinhibitory pathways and promoting T-cell activity; thus, they have great potential for cancer immunotherapy. Therapeutic modulation of cosignaling pathways may shift paradigms from surgical prevention of recurrence to oncological intervention. Herein, we review the available evidence from a therapeutic perspective and focus on immune microenvironment perturbation by immunosuppressants and checkpoint inhibitors. Partial and reversible interleukin-2 signaling blockade is the mainstream strategy of immunosuppression for graft protection. Programmed cell death protein 1 (PD-1) is abundantly expressed on human liver allograft-infiltrating T-cells, which proliferate considerably after programmed death-ligand 1 (PD-L1) blockade. Clinically, checkpoint inhibitors are used in heart, liver, and kidney recipients with various cancers. Rejection can occur after checkpoint inhibitor administration through acute T-cell-mediated, antibody-mediated, or chronic allograft rejection mechanisms. Nevertheless, liver recipients may demonstrate favorable responses to treatment for HCC recurrence without rejection. Pharmacodynamically, substantial degrees of receptor occupancy can be achieved with lower doses, with favorable clinical outcomes. Manipulation of the immune microenvironment is a therapeutic niche that balances seemingly conflicting anticancer and graft protection needs. Additional translational and clinical studies emphasizing the comparative effectiveness of signaling networks within the immune microenvironment and conducting overall assessment of the immune microenvironment may aid in creating a therapeutic window and benefiting future liver recipients with HCC recurrence.
Keywords: hepatocellular carcinoma; immunotherapy; liver transplantation; microenvironment.