Neoadjuvant Immunotherapy Shows Promise as Bridge to Liver Transplant in HCC, but Rejection Risk Demands Caution
Key Insights
Neoadjuvant immune checkpoint inhibitors (search) achieved downstaging in 75%-82% of HCC patients and radiologic responses up to 94%, with three-year post-transplant survival exceeding 85%.
Acute rejection occurred in 16%-28% of patients receiving pre-transplant ICIs, with washout intervals under 30-90 days linked to higher rejection rates.
Adjuvant ICI use post-transplant remains highly uncertain, with rejection in ~25% of cases and mortality of 10%-12%, based on limited case reports.
Immune checkpoint inhibitors (search) (ICIs) administered before liver transplantation can substantially improve tumor downstaging and expand transplant eligibility for patients with hepatocellular carcinoma (search) (HCC), but the approach carries a significant risk of allograft rejection that demands careful patient selection and strict washout protocols, according to a comprehensive review published in Hepatobiliary & Pancreatic Diseases International.
Researchers from the Liver Transplant and Hepatobiliary Surgery Program at the Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai (search), New York, synthesized evidence from clinical trials, cohort studies, meta-analyses, and case series published through August 2025. Their analysis, published online on October 19, 2025, defines both the therapeutic potential and immunologic hazards of integrating immunotherapy into the liver transplantation pathway.
Strong Oncologic Responses in the Neoadjuvant Setting
Across early-phase trials and multicenter cohorts, neoadjuvant ICI therapy produced encouraging results. Downstaging success rates ranged from 75% to 82%, with radiologic tumor responses reaching as high as 94% and pathologic complete or major responses observed in 35% to 88% of patients. One-year post-transplant survival reached approximately 95%, while three-year survival stabilized between 70% and 80%. Long-term graft survival remained robust, exceeding 85% at three years following transplantation with prior ICI exposure.
These outcomes suggest that ICIs can meaningfully enhance transplant candidacy among patients who would otherwise be excluded due to tumor burden exceeding the Milan criteria or disease progression during organ waiting periods.
Rejection Risk and the Critical Role of Washout Timing
The safety signal is equally prominent. Acute rejection episodes occurred in 16% to 28% of patients across large published series, and an individual patient data meta-analysis reported a rejection incidence of 26.4%. The review identifies washout duration—the interval between the last ICI dose and transplantation—as a pivotal determinant of risk. Intervals shorter than 30 to 90 days correlated with markedly elevated rejection rates.
The authors emphasized that the field is moving from asking whether immunotherapy can work before transplant to defining how it can be used safely. They stated that ICIs may become a valuable bridge for patients whose tumors respond well and who can observe an adequate washout period before surgery, but stressed that this approach should not be treated as routine care.
Adjuvant Immunotherapy: A Cautionary Picture
Evidence for adjuvant ICI use after liver transplantation remains sparse and largely limited to case reports. Among these, rejection episodes were reported in approximately 25% of cases, with mortality rates estimated between 10% and 12%. These findings underscore the treacherous immunologic landscape in the context of graft tolerance and highlight the need for translational research into safer post-transplant immunomodulatory strategies.
Alternative Approaches and Future Directions
Alternative immune-based therapies, including natural killer (NK) cell adoptive transfer and cytokine-induced killer (CIK) cells, may offer antitumor benefits with potentially lower risk of graft rejection by exploiting innate immune effector functions rather than T-cell checkpoint blockade. The review supports a cautious, individualized model in which immunotherapy is used only when oncologic benefit and immunologic risk can be carefully balanced.
The authors called for prospective randomized controlled trials to validate neoadjuvant immunotherapy as a safe and effective strategy. If confirmed, such an approach could redefine transplant eligibility criteria and reduce waitlist dropout rates due to tumor progression. For now, the safest strategy requires experienced transplant centers, multidisciplinary decision-making, close monitoring of alpha-fetoprotein (search) trends and imaging response, and careful adjustment of immunosuppression around transplantation.