Advances in liver transplant oncology: Biology-driven selection, systemic therapy integration, and future trial frameworks

Liver transplantation (LT) has evolved from a contraindicated intervention to an established curative modality for carefully selected hepatic malignancies.The Milan criteria-restricting LT to a single hepatocellular carcinoma (HCC) lesion ≤5 cm or up to three lesions ≤3 cm-achieved 5-year overall survival (OS) of 70%-80% with recurrence below 15%, establishing that biologic selection, not anatomic burden, determines transplant candidacy.This review synthesizes updated evidence across several hepatic malignancies-HCC, perihilar cholangiocarcinoma (pCCA), intrahepatic cholangiocarcinoma (iCCA), combined hepatocellular-cholangiocarcinoma (cHCC-CCA), hepatic epithelioid hemangioendothelioma (HEHE), colorectal liver metastases (CRLM), and neuroendocrine liver metastases (NELM)-drawing exclusively recent literature.Across all tumor types, dynamic biomarkers including AFP-L3, des-γ-carboxyprothrombin (DCP), and circulating tumor deoxyribonucleic acid (ctDNA) consistently outperform static morphologic criteria for recurrence prediction.The 2024 TransMet randomized controlled trial delivered a landmark 5-year OS of 73% versus 9% with chemotherapy alone in unresectable CRLM (hazard ratio 0.37; p<0.001), extending curative LT beyond primary hepatic malignancies.In HCC, the VITALITY study (2025) demonstrated that pre-LT immune checkpoint inhibitor (ICI) therapy down-staged 75.6% of patients beyond Milan criteria; however, peri-transplant ICI exposure carries rejection rates of 17%-30%, mandating a minimum 90-day washout period.The IMbrave050 adjuvant immunotherapy trial-initially positive at interim analysis-showed no sustained survival benefit at longer follow-up, underscoring the non-translatability of advanced disease data to transplant settings.For pCCA, the Mayo neoadjuvant protocol achieves 5-year OS of 65%-82%, while FGFR2 and IDH1-directed therapies have enabled proof-of-concept transplantation in iCCA.Primary hepatic angiosarcoma remains an absolute contraindication, exemplifying that biology-not location-defines candidacy.mTORbased immunosuppression demonstrates meta-analytic recurrence benefit in HCC recipients, though prospective validation across other tumor types is lacking.Four prospective trial frameworks are proposed: HCC-ICI-Bridge, TransMet-Expand, iC-CA-TARGET, and NELM-sequencing.Responsible expansion of transplant oncology requires transplant-specific randomized evidence, validated biomarker-guided selection, and ethical stewardship of organ allocation through living donor and out-ofsequence pathways.