Francis Spitz

Importance: Immune checkpoint inhibitors (ICIs) have expanded downstaging options for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), enabling bridging to liver transplantation (LT). However, the immunologic consequences of pre-transplant checkpoint blockade, particularly the risk of allograft rejection mediated by persistent T-cell activation, remain insufficiently characterized, creating a critical knowledge gap at the intersection of immuno-oncology and transplant medicine. Ob jective: To synthesize current evidence on oncologic outcomes, rejection risk, washout intervals, donor-type considerations, and immunosuppression strategies in LT recipients with pre-transplant ICI exposure. Evidence Review: A PRISMA-ScR-guided review was conducted using MEDLINE, Embase, Cochrane Library, and Web of Science from January 2015 through December 2025. Studies reporting outcomes in adult LT recipients with documented pre-transplant ICI exposure for HCC or CCA were included. Methodological quality was descriptively assessed using the Newcastle-Ottawa Scale and JBI tools. Given study heterogeneity, findings were narratively synthesized. Findings: Thirty studies were included. In HCC, neoadjuvant ICI therapy achieved downstaging to Milan criteria in 75.6% of candidates in the largest multicenter cohort (n = 117), with complete pathologic response rates ranging from 23.8% to 40%. Rejection rates ranged from 16.3% to 20.2% in large series but increased to 56.3% with short washout intervals. Washout intervals exceeding 50 days were associated with rejection rates approaching non-ICI controls, while an individual patient meta-analysis of 91 patients estimated each additional week of washout was associated with approximately 8% reduction in rejection risk, suggesting that approximately 94 days may be required to achieve a rejection probability of 20% or less. Rejection occurred at a median of 7–10 days post-transplantation, earlier than typical acute cellular rejection. Three-year overall survival exceeded 85.3% in major cohorts. Donor type was not consistently associated with rejection after adjustment for washout duration. CCA data remain limited. Immune-related adverse events during ICI therapy were associated with increased post-transplant rejection risk. Conclusions: Pre-transplant ICI therapy may expand transplant eligibility in advanced hepatobiliary malignancies but carries time-dependent rejection risk. Current evidence supports a minimum washout interval of at least 50 days, with emerging data favoring 90–94 days when feasible. Prospective multicenter studies, biomarker-guided risk stratification, and standardized immunosuppression protocols are needed to refine patient selection and optimize timing.

Historically, colorectal liver metastases (CRLMs) have been considered a contraindication for liver transplantation (LT), primarily due to limited organ availability and concerns about oncologic efficacy. However, emerging evidence indicates that highly selected patients with unresectable CRLM can achieve long-term survival following LT—often with outcomes superior to those obtained through conventional systemic therapies. To evaluate the evolving role of LT in this setting, we conducted a scoping review of the literature. A comprehensive search was performed across PubMed, Embase, Web of Science, Scopus, and ClinicalTrials.gov, as well as ProQuest Dissertations & Theses and Google Scholar to capture gray literature. The search included English-language articles published between January 2015 and April 2025. Eligible studies included those reporting on the application of LT for patients with unresectable CRLM. This scoping review synthesizes current evidence on patient selection criteria, overall and disease-free survival, recurrence patterns, and emerging biomarkers that may guide transplant eligibility. In addition, we explore innovations in organ utilization—including living donor LT and machine perfusion technologies—that aim to expand access while addressing ethical concerns related to organ allocation. As LT for CRLM transitions from investigational use to clinical implementation, this review outlines the key challenges and future opportunities that will shape its role in the landscape of transplant oncology.

Historically, colorectal liver metastases (CRLM) have been considered a contraindication for liver transplantation (LT), given the limited organ supply and poor oncologic efficacy. Recent studies, however, have demonstrated that highly selected patients with unresectable CRLM can achieve remarkable long-term survival following LT, often surpassing outcomes seen with conventional systemic therapies. This review explores the evolving role of LT for the treatment of unresectable CRLM, examining patient selection criteria, overall survival, disease-free survival, recurrence patterns, and emerging biomarkers that may guide transplant eligibility. Additionally, we discuss innovations in organ utilization, including living donor LT and machine perfusion strategies, to expand access while mitigating ethical concerns surrounding organ allocation. As LT for CRLM transitions from experimental protocols to clinical application, this review highlights key challenges and opportunities that will shape its future role in the field of transplant oncology.

Liver transplantation (LT) in the United States is evolving in response to shifting disease patterns, innovative therapies, and technological advancements. Metabolic-associated fatty liver disease (MAFLD) and alcohol-associated liver disease (ALD) now are the most common indications for LT, reflecting the impact of the obesity epidemic and increased alcohol consumption. Advances in pharmacotherapy for MAFLD and tailored protocols for ALD management are reducing disease progression and improving outcomes. The inclusion of colorectal liver metastases (CRLM) and intrahepatic cholangiocarcinoma (iCCA) as transplant indications highlights progress in chemotherapy and patient selection. Technologies like normothermic machine perfusion (NMP) are expanding the donor pool, while xenotransplantation and organ rehabilitation offer transformative solutions to organ shortages. As the population ages, LT programs must address challenges in older patients and explore minimally invasive approaches for donors and recipients. By integrating innovation and multidisciplinary expertise, LT will continue to provide life-saving care while adapting to the needs of diverse patient populations.