Immunotherapy in liver transplantation for hepatocellular carcinoma: A comprehensive review

Abstract

Immunotherapy has emerged as an important approach in the treatment of hepatocellular carcinoma (HCC), particularly through the use of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 and CTLA-4 pathways. While this therapy offers new hope for patients, it presents unique challenges when integrated with liver transplantation (LT), the definitive treatment for early-stage HCC. Despite LT's curative potential, post-transplant tumor recurrence remains a concern, partly due to the immunosuppressive regimens necessary to prevent graft rejection, which can impair immune surveillance and increase the risk of HCC recurrence and de novo malignancies. Incorporating immunotherapy offers a strategy to enhance antitumor immunity but raises concerns about triggering graft rejection due to immune activation. Nevertheless, the use of ICIs as neoadjuvant therapy before LT has demonstrated promise in downstaging tumors and reducing waitlist dropout rates; however, careful patient selection, optimal timing between ICI administration and LT, and tailored immunosuppressive management are crucial to mitigate the risk of acute graft rejection. In the post-LT setting, ICIs have been examined for treating recurrent HCC, with some data demonstrating promising antitumor responses. Nonetheless, the risk of severe rejection unresponsive to standard immunosuppressive therapies necessitates cautious application and close monitoring. Furthermore, emerging immuno-cell therapies, such as natural killer (NK) cell-based treatments, offer robust antitumor activity with potentially fewer adverse effects compared with T-cell-based therapies. These innovative approaches are under investigation for their ability to enhance immune surveillance and reduce HCC recurrence post-LT. Integrating immunotherapy into the management of HCC among LT recipients holds promise but requires a delicate balance between maximizing antitumor efficacy and minimizing the risk of graft rejection. Future research should focus on establishing standardized protocols for the safe incorporation of immunotherapy in LT patients, optimizing immunosuppressive regimens, and further exploring the potential of immuno-cell therapies to improve long-term outcomes for HCC patients undergoing LT.