Standardized Management Pathway to Prevent Acute Rejection After Liver Transplantation Following ICI Therapy for Downstaging HCC.

Standardized Management Pathway to Prevent Acute Rejection After Liver Transplantation Following ICI Therapy for Downstaging HCC - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Health Care Sci . 2026 Apr 23;5(3):196–206. doi: 10.1002/hcs2.70071 Standardized Management Pathway to Prevent Acute Rejection After Liver Transplantation Following ICI Therapy for Downstaging HCC Ning Wang 1 , Zebin Zhu 1 , Hao Zheng 1 , Can Qi 1 , Xiaodong Yuan 1 , Xuefeng Li 1 , Zhijun Xu 1 , Jiwei Qin 1 , Wei Wu 1 , Jizhou Wang 1 , Ruipeng Song 1 , Zhiyong Guo 2, 3, 4, 5 , Lianxin Liu 1 , Shu‐Geng Zhang 1, ✉ , Björn Nashan 1, 3, 6, ✉ Author information Article notes Copyright and License information 1 The Transplantation Center, First Affiliated Hospital, School of Life Sciences and Medical Center, University of Sciences & Technology of China, Hefei, China 2 Organ Transplant Centre, The First Affiliated Hospital, Sun Yat‐sen University, Guangzhou, China 3 Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, China 4 Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Guangzhou, China 5 NHC Key Laboratory of Assisted Circulation (Sun Yat‐sen University), Guangzhou, China 6 Research Centre of Big Data and Artificial Intelligence of Medicine, The First Affiliated Hospital of Sun Yat‐sen University, Guangzhou, China * Correspondence: Shu‐Geng Zhang ( zsg0517@ustc.edu.cn ), Björn Nashan ( bjoern.nashan@gmail.com ) ✉ Corresponding author. Revised 2026 Jan 27; Received 2025 Nov 6; Accepted 2026 Jan 29; Collection date 2026 Jun. © 2026 The Author(s). Health Care Science published by John Wiley & Sons Ltd on behalf of Tsinghua University Press. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. PMC Copyright notice PMCID: PMC13241823  PMID: 42255043 ABSTRACT Background Immune checkpoint inhibitors (ICIs) have shown promise in downstaging hepatocellular carcinoma (HCC) for liver transplantation (LT), enabling previously ineligible patients to meet transplant criteria. However, their use raises concerns about post‐transplant acute rejection (AR) based on data lacking information regarding standardized management pathways and notably perioperative protocols, including immunosuppression protocols and monitoring. Methods This study evaluated 59 LT recipients divided into three groups (two control groups), including 13 ICI‐exposed patients (third group). All groups followed a standardized immunosuppression protocol and monitoring embedded into an enhanced recovery after surgery (ERAS) protocol, featuring basiliximab and steroid induction, early mammalian target of rapamycin inhibitor (mTOR) use, and reduced tacrolimus dosing. Results Despite varied ICI washout intervals (median 36 days), no AR episodes were observed in any group. One‐year overall survival and recurrence‐free survival were 93%/85% and 100%/85% in standard patients, and 77%/69% in ICI‐exposed patients, respectively. The most frequent complications were biliary and infectious, with no significant intergroup differences. Conclusions These findings suggest that in a standardized clinical pathway with structured immunosuppressive protocols, therapeutic drug monitoring, and early complication surveillance, LT can be safely performed after ICI exposure without increasing rejection risk. The study underscores the need for standardized clinical pathways and consistent reporting of immunosuppressive regimens to optimize outcomes in this emerging patient population. Keywords: acute rejection, enhanced recovery after liver transplantation, hepatocellular carcinoma, immune checkpoint inhibitor therapy, immunosuppression protocol, perioperative protocol, quality management, standardized management pathway Findings indicate that within a standardized clinical pathway integrating structured immunosuppression, therapeutic drug monitoring, and early complication surveillance, liver transplantation after ICI exposure can be performed safely without increased rejection risk. The study highlights the need for harmonized protocols and transparent reporting of immunosuppressive regimens to optimize outcomes. Abbreviations AR acute rejection BAL bronchoalveolar lavage CBD common bile duct CIT cold ischemia time COVID coronavirus disease CT computer tomography DBD donation after brain death DCD donation after circulatory death DSA digital subtraction angiography ERAS enhanced recovery after surgery ERCP endoscopic retrograde cholangiopancreatography HAT hepatic artery thrombosis HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus ICI immune checkpoint inhibitor IQR interquartile range ITT intention‐to‐treat LFT liver function test LT liver transplantation MRCP magnetic resonance cholangiopancreatography mTOR mammalian target of rapamycin inhibitor OS overall survival PJP pneumocystis jirovecii pneumonia RFS recurrence free survival TDM therapeutic drug monitoring TKI tyrosine kinase inhibitor TNM tumor node metastasis 1. Introduction Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer‐related mortality worldwide [ 1 ]. Liver transplantation (LT) remains a curative option for selected patients [ 2 , 3 , 4 ]; however, eligibility is frequently restricted by tumor burden exceeding established criteria such as Milan or University of California, San Francisco benchmarks [ 5 ]. Effective downstaging strategies are, therefore, critical for expanding access to LT [ 6 ]. Immune checkpoint inhibitors (ICIs) have recently emerged as a promising approach for tumor downstaging in HCC [ 7 , 8 ]. Numerous studies [ 7 , 8 ] have reported that ICIs allow approximately 60% of patients to achieve transplant criteria and yield complete pathological responses in over 30%. These findings have fueled interest in integrating ICIs into pre‐LT oncologic protocols. However, ICI therapy introduces unique immunologic risks, particularly enhanced T‐cell activation that might facilitate acute rejection (AR) after LT. Recent analyses report AR incidence of 26%–28% among ICI‐exposed recipients, often occurring early post‐transplant and requiring intensive immunosuppressive (IS) rescue therapy [ 7 , 8 ]. Short ICI‐to‐LT intervals (< 94 days) and younger age have been identified as major risk factors [ 7 ]. Yet, most available data are from case series or meta‐analyses without control groups, and detailed IS protocols, and standardized rejection grading are rarely reported, while therapeutic drug monitoring (TDM) is not reported at all. These gaps—particularly the lack of standardized clinical pathways and perioperative strategies—hinder meaningful outcome analysis in this potentially high‐risk population, leading to a misplaced focus on immunological risk factors rather than addressing structural deficiencies in patient management. Enhanced recovery after surgery (ERAS) pathways are well established in our institution and have improved perioperative outcomes in general in LT by standardizing fluid management, analgesia, and early mobilization [ 9 , 10 , 11 , 12 , 13 , 14 ] However, current ERAS guidelines lack recommendations for IS optimization, TDM or management of patients previously exposed to ICIs [ 9 , 10 , 11 , 12 ] merely focusing on anesthesia and surgery to shorten stay in hospital and hence cut costs. This omission is clinically relevant, as early postoperative liver enzyme elevation in this cohort may represent rejection, infection, or surgical complications—conditions requiring different management approaches. In contrast, we had developed an ERAS protocol, particularly including IS and TDM, to close this clinical gap [ 13 ]. This study analyzes AR events in HCC patients undergoing LT under a standardized ERAS protocol [ 13 , 14 ], comparing three downstaging strategies: (1) locoregional therapy, (2) targeted therapy, and (3) targeted therapy combined with ICIs. We place particular emphasis on the ICI group, evaluating whether structured IS regimens, early mTOR conversion, and rigorous TDM can mitigate AR risk in this challenging patient population. 2. Methods 2.1. Patient and Donor Demographics Between October 2018 and December 2023, 69 patients underwent (LT) for HCC, of whom 59 received tumor downstaging prior to LT. The cohort was categorized into three groups based on downstaging therapy: Group 1 ( n = 40): Transarterial chemoembolization (TACE), radiofrequency ablation (RFA), or resection; Group 2 ( n = 6): Targeted therapy alone; and Group 3 ( n = 13): Combination of targeted therapy and ICIs. Inclusion criteria were: (1) age between 18 and 75 years; (2) histologically confirmed HCC; and (3) receipt of at least one course of pre‐LT ICI therapy for tumor downstaging or as bridging treatment while awaiting LT. Exclusion criteria were: (1) combined or multivisceral transplantation; (2) history of malignancy other than HCC; (3) ABO‐incompatible transplantation; and (4) presence of extrahepatic metastases before LTx. Donor characteristics were collected and analyzed for all LTs across the three study groups. Variables included donor age, sex, graft type, and cold ischemia time (CIT). Donors were classified by graft source as donation after brain death (DBD) or donation after circulatory death (DCD). The percentage of donors aged > 50 years and the proportion of male donors were recorded for each group. CIT was reported as the median with interquartile range (IQR). Group 1 ( n = 40) primarily received grafts from DBD donors (72.5%), with DCD grafts accounting for 27.5%. 2.2. Posttransplant Management and Follow‐Up Posttransplant management followed our ERAS protocol as described elsewhere [ 13 ]. Briefly, it included the postoperative management in addition to physiological monitoring, nutrition, laboratory monitoring, analgesia, stress prophylaxis, antibiotics, antivirals or antimycotics, and rehabilitation training. The immunosuppressive regimen consisted of basiliximab (20 mg each, postoperative day [POD] 0 and 4), Tacrolimus (POD 1, 3 mg bid), MMF (POD 1500 mg bid) switched to Sirolimus, between 10 and 20 days after transplantation based on previous experience [ 15 , 16 , 17 ], and steroids rapidly tapered to maintenance 5 mg qd at pod 7. Tacrolimus and Sirolimus were monitored by C0, aiming for exposure between 3 and 8 ng/mL. After discharge, patients were followed up in our outpatient clinic on a regular schedule. In addition to (II) immunosuppression, as detailed by Yuan et al. [ 13 ], the ERAS protocol includes postoperative recommendations for (I) postoperative monitoring, (III) nutrition, (IV) diagnostic monitoring, (V) stress ulcer prophylaxis, (VI) analgesia, (VII) anticoagulation, (VIII) antiviral, antibiotic, and antifungal therapy, and (IX) rehabilitation training. Clinical and laboratory findings of the patients were reviewed during daily chart rounds using comprehensive Excel‐based documentation to provide a structured chronological overview and facilitate clinical decision‐making. 2.3. Outcomes The primary endpoint was the incidence of posttransplant rejection; secondary endpoints were overall survival (OS) and recurrence‐free survival (RFS). Comparisons of OS and RFS between the three groups were not performed due to significant differences in tumor burden. In cases of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or cholestatic markers gamma glutamyltransferase (γGT), alkaline phosphatase (ALP), or bilirubin (Bili), exceeding twice the upper limit of normal, immunosuppressive drug exposure was evaluated. A Doppler ultrasound was performed, followed by contrast‐enhanced CT or MRCP if needed, to exclude confounding factors such as hepatic artery thrombosis, portal vein (PV) stenosis/thrombosis, biliary strictures or leaks, and hepatic vein outflow obstruction. Drug toxicity was ruled out through assessment of drug levels. AR was suspected when imaging findings were normal and immunosuppressive exposure had been subtherapeutic within the preceding 48–72 h. A confirmed episode was defined as one requiring intensified immunosuppressive therapy, with subsequent normalization or near‐normalization of liver function within 4 weeks after treatment. Biopsies would have been performed only for cause, i.e., elevation of LFT under therapeutic range exposure to immunosuppression and in the absence of alternative explanations such as infection, biliary complications, drug toxicity, or vascular stenosis. This approach is based on our previous findings, that immunological activity shortly after transplantation does not predict AR but might reflect the presence of donor lymphocytes along with subclinical GvHD [ 18 , 19 , 20 ]. 2.4. Statistical Analysis In this study, all statistical analyses were conducted using SPSS 25.0 and GraphPad Prism 8.0. Demographic information and general baseline characteristics were analyzed by descriptive statistical analysis, and quantitative indicators were described by arithmetic mean, standard deviation, quartile, credible interval, and other statistical indicators; qualitative indicators were the number of cases, frequency, composition ratio, and percentage rate, and other statistical indicators were described. We considered a p ‐value of 0.05 as statistically significant in this study. 2.5. Ethic Statement The study protocol was approved by the ethics committee of First Affiliated Hospital, University of Science and Technology of China (# 2025‐RE‐229), which waived the requirement for informed consent due to the retrospective nature of this study. The study was conducted in accordance with the ethical guidelines of the World Medical Association's 2013 World Declaration of Helsinki. 2.6. Organ Procurement Statement None of the organs was procured from executed prisoners; all organs were procured after informed consent from family members of the donors. 3. Results 3.1. Baseline Characteristics of Liver Transplant Recipients and Donors A total of 59 liver transplant recipients were divided into three groups. Table 1 summarizes their baseline characteristics, including sex, age, model for end‐stage liver disease (MELD) score, and underlying disease etiology. Group 1 included 40 recipients, predominantly male (38, 95%). The mean age was 50.4 years. The median MELD score was 10 with a range of 6–18. The primary etiology of liver disease was hepatitis B virus (HBV), present in 38 patients (95%), while 2 patients (5%) had hepatitis C virus (HCV); no other causes were reported in this group. Group 2 comprised 6 recipients, all male (100%), with a mean age of 46.0 years. The MELD score also had a median of 10 (range: 7–14). HBV was identified in 5 patients (83.3%), while 1 patient (16.7%) had other etiologies. No cases of HCV were reported. Group 3 consisted of 13 patients, with 12 (92.3%) male. The mean age was 52.8 years, and the MELD score ranged from 8 to 22, with a median of 12. HBV remained the leading etiology (12 patients, 92.3%), while 1 patient (7.7%) had HCV‐related liver disease. No other etiologies were reported. Table 1. Baseline characteristics of recipients and donors. Parameter Group 1 Group 2 Group 3 Recipients ( n ) 40 6 13 Sex, male 38 (95) 6 (100) 12 (92.3) Age (mean ± SD) 50.4 ± 9.5 46.0 ± 11.5 52.8 ± 10.3 Age > 50 years 23 (57.5) 3 (50) 10 (76.9) MELD score 10 (6–18) 10 (7–14) 12 (8–22) Etiology HBV 38 (95) 5 (83.3) 12 (92.3) HCV 2 (5) — 1 (7.7) Other — 1 (16.7) — Donors ( n ) 40 6 13 Sex, male 31/ (77.5%) 4 (66.7%) 9 (75%) Age 53.9 ± 8 56.5 ± 5.9 48.6 ± 16 Age > 50 years 28 (70%) 5 (83.3%) 8 (61.5%) Graft type DBD 29 (72.5%) 5 (83.3%) 9 (69.2%) DCD 11 (27.5%) 1 (16.7%) 4 (30.3%) CIT, min 315 (246–465) 268 (223–410) 297 (286–378) Open in a new tab Note: Data are presented as n (%) or median (IQR) or mean ± SD. Recipients: n = 59; N (%); Donor: n = 59; N (%) or median (IQR). Abbreviations: CIT, cold ischemia time; DBD, donation after brain death; DCD, donation after cardiocirculatory death; HBV, hepatitis B virus; HCV, hepatitis C virus. Overall, HBV was the predominant etiology across all groups, and male recipients comprised the vast majority. MELD scores were generally low to moderate across groups. Donor characteristics across the three recipient groups are summarized in Table 1 . A total of 59 donors were included in the analysis, with data reported as number (percentage) or median (IQR), where appropriate. Group 1 included 40 donors. The majority were older than 50 years (28, 70%) and male (31, 77.5%). Mean age for Groups 1, 2, and 3 were 53.9, 56.9, and 48.6 years, respectively. DBD was the predominant graft type, used in 29 cases (72.5%), whereas DCD accounted for 11 cases (27.5%). The median CIT was 315 min (IQR: 246–465). Group 2 comprised 6 donors, with 5 (83.3%) over 50 years of age and 4 (66.7%) male. DBD was the graft type in 5 donors (83.3%), while only 1 donor (16.7%) provided a DCD graft. The CIT had a median value of 268 min (IQR: 223–410). Group 3 included 13 donors. Of these, 8 (61.5%) were older than 50 years, and 9 (75%) were male. DBD grafts were used in 9 cases (69.2%), and DCD grafts in 4 cases (30.8%). The median CIT was 297 min (IQR: 286–378). Donor profiles were generally comparable across the three groups, with no significant differences observed in age distribution, sex, graft type, or CIT. 3.2. Tumor Characteristics and TNM Staging of HCC Tumor‐related variables, including alpha‐fetoprotein (AFP) levels, tumor size, number, TNM stage, differentiation grade, microvascular invasion, and Milan criteria status, are summarized for all three groups (Table 2 ). Table 2. Tumor characteristics, AFP levels (pre‐ and post‐liver transplantation), and TNM staging across study groups ( n = 59). Group 1 Group 2 Group 3 Parameter n = 40 n = 6 n = 13 p Pre‐LT AFP 4.5 (2.9–11.9) 7.5 (2.1–98.4) 14.7 (3.6–252.3) 0.005 Post‐LT AFP 2.9 (1.1–6.2) 3.4 (2.5–6.0) 4 (2.4–39.9) 0.038 Pre‐LT tumor diameter 3 (1.3–5.5) 3.38 (2.5–4.0) 6.9 (4.0–17.0) 0.021 Pre‐LT number of tumors 0.201 < 3 25 (62.5) 3 (50.0) 8 (61.5) ≥ 3 7 (17.5) 3 (50.0) 5 (38.5) Tx 8 (20.0) — — TNM staging 0.333 IA‐IB 19 (47.5) 3 (50) 3 (23.1) II 11 (27.5) 3 (50) 2 (15.4) IIIA‐IIIB 2 (5) — 5 (38.5) IVA‐IVB — — 1 (3) No tumor in pathology 8 (20) — 2 (15.4) Tumor differentiation grade 0.016 Gx 21 (52.5) 2 (33.3) 2 (15.4) G1 1 (2.5) 1 (16.7) 2 (15.4) G2 13 (32.5) 3 (50) 5 (38.4) G3 5 (12.5) 0 4 (30.8) Microvascular invasion 6 (15) 2 (33.3) 2 (15.4) 0.123 Within Milan 37 (92.5) 5 (83.3) 7 (53.8) 0.005 Outside Milan 3 (7.5) 1 (16.7) 6 (46.2) Open in a new tab Note: Data are presented as n (%) or median (IQR) or mean ± SD. Recipients: n = 59; N (%); Patients ( n = 59, %); AFP—median (IQR); tumor diameter in cm, p values were derived from the logistics regression analysis, p < 0.05 shows statistical significance. Abbreviations: AFP, alpha fetoprotein; LT, liver transplantation; TNM, universal system for staging solid tumors, describing the cancer's spread using T (Tumor size/invasion), N (Node involvement in nearby lymph nodes), and M (Metastasis to distant sites). Group 1 ( n = 40) had the most favorable tumor profile. Pre‐transplant AFP levels were low, with a median of 4.5 ng/mL (IQR: 2.9–11.9), and further decreased post‐transplant to 2.8 ng/mL (IQR: 1.1–6.2). Tumor burden was modest: the median tumor diameter was 3.0 cm (IQR: 1.3–5.5), and 65% of patients had a single lesion. Only 12.5% had more than two tumors. Histologically, tumors were generally well to moderately differentiated (G1: 25%; G2: 60%), with only 15% showing microvascular invasion. 92.5% of patients remained within Milan criteria at the time of transplantation. TNM staging confirmed early disease, with 75% of patients classified as Stage IA or II. Overall, this group demonstrated low‐risk tumor biology and high protocol adherence. Group 2 ( n = 6) showed intermediate tumor characteristics. The median AFP pre‐transplant was 7.5 ng/mL (IQR: 2.1–98.4), decreasing post‐transplant to 4.3 ng/mL (IQR: 2.2–7.8). Tumor size was relatively small (median diameter 3.38 cm, IQR: 2.5–4.0), though half of the patients had two or more lesions. Histologic analysis revealed a broader spectrum of differentiation (G1: 33.3%, G2: 16.7%, G3: 50.0%), and 33.3% had microvascular invasion. 83.3% of patients were within the Milan criteria. TNM staging was more advanced than in Group 1, with 50% of patients in Stage I and the remainder in Stage II. These findings suggest moderate tumor aggressiveness in this group. Group 3 ( n = 13) exhibited the highest‐risk tumor features. Pre‐transplant AFP levels were markedly elevated (14.7 ng/mL, IQR: 3.6–252.3) and remained high post‐transplant (5.6 ng/mL, IQR: 2.2–41.7). The median tumor diameter was 6.9 cm (IQR: 4.0–17.0), significantly larger than in Groups 1 and 2. Moreover, 38.5% of patients had three or more lesions. Tumor differentiation was skewed toward higher grades (G3: 30.8%), although one case had no residual tumor on explant (pT0). Microvascular invasion was seen in 15.4% of patients. Only 53.8% of Group 3 patients were within the Milan criteria. TNM staging revealed more advanced disease: 38.5% were classified as Stage IIIA or IIIB, and 3% as Stage IVA or IVB. This group represented the highest tumor burden and most advanced pathology among the cohorts. Statistical analysis revealed significant differences in pre‐LT AFP ( p = 0.005), post‐LT AFP ( p = 0.038), tumor diameter ( p = 0.021), and Milan criteria status ( p = 0.005) among the three groups. No significant differences were observed for tumor number ( p = 0.201), differentiation grade ( p = 0.333), or microvascular invasion ( p = 0.123). Despite numerical differences, no significant differences were observed among groups in terms of tumor number, differentiation, or microvascular invasion. However, Group 3 exhibited more advanced disease features in terms of tumor burden, including higher AFP levels, larger tumors, and a greater proportion of patients outside Milan criteria. Hence, a direct comparison of OS and RFS between the three groups was not performed. 3.3. ARs, Complications, and Outcomes Table 3 summarizes the immunosuppressive strategies, complication profiles, and 1‐year clinical outcomes across the three patient groups. All patients in Group 1 ( n = 40), Group 2 ( n = 6), and Group 3 ( n = 13) received induction therapy with basiliximab and steroids. The majority of patients in Group 1 (87.5%) received a tacrolimus–sirolimus (Tac + Sir) switch protocol, compared to all patients in Groups 2 and 3 (100%). Tac trough levels were reported at POD 7, 14, and at discharge. In Group 1, Tac levels decreased over time: 7.5 ng/mL (IQR: 4.0–16.3) at POD 7, 7.3 (IQR: 4.3–15.4) at POD 14, and 6.6 (IQR: 4.1–15.2) at discharge. Group 2 had comparable levels: 6.7 (IQR: 2.6–11.4), 6.5 (IQR: 3.5–10.7), and 6.3 (IQR: 4.4–8.4) at the respective timepoints. Group 3 exhibited Tac levels of 8.2 (IQR: 3.0–17.5) at POD 7, 6.6 (IQR: 4.5–9.0) at POD 14, and 7.0 (IQR: 6.0–9.7) at discharge. Sirolimus (Sir) levels were available at POD 14, median Sir levels were 6.4 ng/mL (IQR: 3.8–11.9) in Group 1 and 8.8 (IQR: 3.9–13.0) in Group 2. At POD 30, the values were 6.7 (IQR: 3.3–10.6) and 5.9 (IQR: 4.3–9.4), respectively, and for Group 3 7.0 (IQR: 2.9–12.0). Table 3. Immunosuppression, trough levels, complications, and endpoints (acute rejection, survival). Group 1 Group 2 Group 3 Parameter N = 40 N = 6 N = 13 p IS agents Basiliximab and steroids 40 (100) 6 (100) 13 (100) Tac + Sir (switch) 35 (87.5) 6 (100) 12 (92.3) Tac level (ng/mL) POD 7 7.5 (4.0–16.3) 6.7 (2.6–11.4) 8.2 (3.0–17.5) 0.563 POD 14 7.3 (4.3–15.4) 6.5 (3.5–10.7) 6.6 (4.5–9.0) 0.876 Discharge 6.6 (4.1–15.2) 6.3 (4.4–8.4) 7.0 (6–9.7) 0.551 Siro level (ng/mL) POD 14 6.4 (3.8–11.9) 8.8 (3.9–13.0) — 0.561 POD 30 6.7 (3.3–10.6) 5.9 (4.3–9.4) 7.0 (2.9–12.0) 0.183 Complications (C‐D classification) 0.550 I–II 22 (55.0) I–II 4 (66.7) I–II 7 (53.8) III 15 (37.5) III 2 (33.3) III 4 (30.8) IV 3 (7.5) — IV 2 (15.4) Acute rejection 0 0 0 Outcomes (1‐year) OS 93% 100% 77% RFS 85% 84% 69% Open in a new tab Note: Data are presented as n (%) or median (IQR). Recipients: n = 59, N (%); Recipients: n = 59, N (%) or median and IQR, p ‐values were derived from the logistics regression analysis, p < 0.05 shows statistical significance; Abbreviations: C‐D, Clavien‐Dindo; OS, overall survival; POD, postoperative day; RFS, recurrence free survival; Sir, Sirolimus; Tac, Tacrolimus. Complication rates, classified according to the Clavien‐Dindo system, were comparable across groups. In Group 1, 22 patients (55.0%) had Grades I–II complications, 15 (37.5%) had Grade III, and 3 (7.5%) experienced Grade IV events. Group 2 had 4 patients (66.7%) with Grades I–II and 2 (33.3%) with grade III complications. Group 3 reported 7 patients (53.8%) with Grades I–II, 4 (30.8%) with Grade III, and 2 (15.4%) with Grade IV complications. Notably, no cases of AR were observed in any group. One‐year OS and RFS rates were as follows: Group 1, 93% OS and 85% RFS; Group 2, 100% OS and 84% RFS; and Group 3, 77% OS and 69% RFS. There were no significant differences in immunosuppression levels, complication severity, or short‐term outcomes among the three groups. 3.4. Postoperative Complications According to Clavien‐Dindo Classification Table 4 details the postoperative complications observed across the three study groups, classified according to the Clavien‐Dindo (C‐D) system. A wide spectrum of surgical and infectious complications occurred during the post‐liver transplant course, ranging from Grade III to IV severity. No Grade V (mortality) events were reported. Group 1 ( n = 18 with complications) experienced a variety of surgical and infectious complications, most frequently related to the biliary tract. These included common bile duct (CBD) stenosis ( n = 6), hepatic artery thrombosis (HAT, n = 2), ischemic‐type biliary lesions (ITBL), and CBD + PV stenosis. Infectious complications such as lung infections ( n = 3), HHV‐6 brain infection, and abdominal or incision site infections were also observed. Complications were primarily C‐D Grade III ( n = 15) and Grade IV ( n = 3). Treatments ranged from endoscopic retrograde cholangiopancreatography (ERCP) and bronchial alveolar lavage (BAL) to abdominal exploration and PV stenting. Group 2 ( n = 2 with complications) reported CBD stenosis and COVID‐19 infection, both classified as C‐D Grade III. Management included ERCP and BAL. Group 3 ( n = 6 with complications) presented a mix of infectious, vascular, and metastatic complications. These included COVID‐related lung infection, bile leakage, intrahepatic hematoma [ 21 ], adrenal and lung metastases, and CBD stenosis. All were classified as C‐D Grade III ( n = 5) or IV ( n = 1). Treatment modalities included ERCP, puncture, BAL, and radiation therapy. Table 4. Complications—Clavien Dindo classifications. Patients Complications C‐D POD Treatment Group 1 1 HHV‐6 brain infection IV 20 Lumbar puncture 2 CBD stenosis III 21 ERCP 3 HAT III 1 Abdominal exploration 4 CBD stenosis III 150 ERCP 5 HAT III 1 Abdominal exploration 6 ITBL III 147 ERCP 7 Lung infection III 10 BAL 8 Bile leakage + pancreatic leakage IV 1 Abdominal exploration 9 CBD stenosis III 180 ERCP 10 Lung infection III 9 BAL 11 CBD + PV stenosis III 28 ERCP + PV stent 12 Incision infection III 35 Debridement 13 CBD stenosis III 25 ERCP 14 CBD + PV stenosis IIII 31 ERCP + PV stent 15 Lung infection III 14 BAL 16 GI leakage IV 11 Abdominal exploration 17 CBD stenosis III 17 ERCP 18 Abdominal infection III 13 Puncture Group 2 1 CBD stenosis III 90 ERCP 2 COVID‐19 infection III 57 BAL Group 3 1 Lung—COVID infection IV 85 BAL 2 Intrahepatic hematoma, bile leakage III 10 ERCP + DSA 3 Adrenal metastasis III 157 Radiation 4 Lung metastasis III 120 Puncture 5 CBD stenosis III 32 ERCP 6 Lung infection III 9 BAL Open in a new tab Abbreviations: BAL, bronchoalveolar lavage; CBD, common bile duct; COVID, coronavirus disease; DSA, digital subtraction angiography; ERCP, endoscopic retrograde cholangiopancreatography; GI, gastrointestinal; HAT, hepatic artery thrombosis; HHV, human herpesvirus; ITBL, ischemic‐type bile duct lesion; PV, portal vein. Although complication types varied slightly by group, no significant differences were observed in the severity (C‐D classification) or frequency of complications among the three groups. Biliary complications were the most common across all groups, and most patients were managed successfully with minimally invasive interventions. 3.5. ICI Therapy and Transplantation Outcomes Thirteen patients received ICI therapy prior to LT. Table 5 summarizes the ICI regimens, interval between last ICI administration and transplantation, number of ICI cycles, complications, incidence of graft rejection, and 1‐year survival outcomes. Table 5. Immune checkpoint inhibitor therapy—Number of cycles and interval to transplant. N ICI Interval time (Days) ICI cycles Allograft rejection Complication 1‐year survival 1 Camrelizumab + Sorafenib 30 6 N Atypical pneumonia (PJP); renal insufficiency N 2 Camrelizumab + Lenvatinib 28 7 N N Y 3 Lenvatinib Tislelizumab 67 15 N Biliary leakage; intrahepatic hematoma Y 4 Camrelizumab + Lenvatinib/Donafenib 43 11 N Left adrenal metastasis Y 5 Pembrolizumab + Lenvatinib 10 3 N Multiple metastases in the liver and lungs N 6 Triprolizumab/Tislelizumab + Lenvatinib 65 26 N N Y 7 Sintilimab + Atezolizumab + Bevacizumab 87 3 N N Y 8 Lenvatinib + Tislelizumab 57 2 N N Y 9 Sintilimab + Bevacizumb 36 10 N Abdominal metastasis Y 10 Pembrolizumab + Donafenib 14 1 N Postop septicemia N 11 Envafolimab + Donafenib 42 12 N Partial resection of left renal carcinoma. Y 12 Sintilimab + Donafenib 15 4 N N Y 13 Camrelizumab 31 4 N Intrahepatic recurrence Y Open in a new tab Note: Y: yes; N: no. The interval between the last ICI dose and LT ranged from 10 to 87 days, with a median of approximately 36 days. The number of ICI treatment cycles varied widely, from 1 to 26 cycles, reflecting heterogeneity in treatment duration and regimen complexity. All patients received combination therapies involving at least one ICI and a tyrosine kinase inhibitor (TKI) such as Lenvatinib, Donafenib, or Sorafenib. Commonly used ICIs included Camrelizumab, Tislelizumab, Sintilimab, Triprolizumab, and Pembrolizumab. Notably, no cases of acute allograft rejection were observed in this cohort, despite recent ICI exposure prior to transplantation. Postoperative complications were documented in several patients, including Infectious complications: Pneumocystis jirovecii pneumonia (PJP) and lung infection (Patient 1), biliary leakage and intrahepatic hematoma [ 21 ] (Patient 3), and abdominal metastases (Patient 9). Oncologic progression: Multiple metastases (Patient 5), adrenal metastasis (Patient 4), and recurrence of HCC (Patient 13). Other complications: Renal insufficiency (Patient 1), partial resection for renal carcinoma (Patient 11). No other signals, e.g., elevation of LFTs or complications that might be linked to the previous ICI therapy, were observed. One‐year survival was achieved in 10 of the 13 patients (77%). Among the three patients who did not survive to 1 year, one experienced cancer‐related progression, one died postoperatively from septicemia of unknown origin, and one died of PJP pneumonia. These findings suggest that pre‐transplant ICI therapy did not lead to allograft rejection, and that carefully timed transplantation following ICI exposure may be feasible, although the risk of cancer progression and perioperative complications warrants close monitoring. 4. Discussion The increasing use of ICIs for HCC has substantially widened the eligibility for LT, particularly for patients previously considered beyond conventional criteria [ 2 , 3 , 4 , 5 , 6 , 7 ]. Agents targeting the PD‐1/PD‐L1 axis have demonstrated significant efficacy in tumor downstaging, sometimes achieving complete pathological response, enabling LT as a curative option. However, the immunologic sequelae of ICI therapy—specifically the enhancement of T‐cell activation and alloreactivity—might pose serious challenges in the post‐transplant setting. AR has emerged as one of the most concerning complications, raising questions about optimal timing and IS strategies in this high‐risk group. Recent clinical evidence seems to underscore these concerns. A multicenter prospective study of 83 patients across 14 transplant centers reported an AR rate of 27.7%, with a marked increase in patients transplanted within 30 days of ICI therapy [ 8 ]. Similarly, a large meta‐analysis encompassing 250,966 adverse events confirmed AR as a significant post‐LT risk, reporting an overall incidence of 26.4%, with older age and extended washout intervals (> 94 days) appearing protective [ 7 ]. While these findings highlight an association between ICIs and AR, interpretation is hampered by methodological limitations: heterogeneous ICI protocols, heterogeneous IS regimens or no information regarding the IS regimen, lack of TDM, incomplete biopsy confirmation, and lack of control groups. In most cases, AR episodes were diagnosed clinically, without standardized grading or response assessment [ 22 , 23 ]. These gaps make it difficult to disentangle whether rejection risk is primarily driven by ICI exposure or by inadequate IS strategies, respectively, and the lack of standardized clinical pathways. The lack of perioperative strategies, particularly the reporting of structured IS protocols in ICI‐exposed LT patients, mirrors earlier challenges seen in kidney and LT research. For example, early studies on mTOR inhibitors such as sirolimus and everolimus frequently failed to report critical endpoints such as wound healing, metabolic adverse events, and precise dosing schedules, limiting their applicability [ 24 ]. Similar inconsistencies now exist in ICI‐related LT literature, where IS regimens, drug levels, and biopsy‐proven rejection rates are underreported. Without harmonized definitions and standardized documentation, including control groups, comparing outcomes across centers remains difficult, and the development of evidence‐based guidelines is hindered. Despite these gaps, the SILVER trial [ 25 ] (ITT) and two randomized, prospective, controlled trials, the H2304 study [ 26 ], and the HEPHAISTOS study [ 27 ] provide a valuable framework for managing IS in high‐risk LT cohorts. Particularly, the HEPHAISTOS study demonstrated that early initiation of everolimus with reduced tacrolimus exposure preserves renal function and effectively prevents AR, with reported rates as low as 7.1% [ 25 , 26 , 27 , 28 ]. Furthermore, the oncologic safety of mTOR‐based regimens has been established, with evidence suggesting reduced recurrence risk in HCC patients post‐LT [ 22 , 23 , 28 ]. A particular strength of these studies was that they focused on clearly described primary and secondary endpoints, mandatory IS protocols and TDM, stratification of risk groups (e.g., HCV), and prospective monitoring and reporting of complications [ 29 ]. Building on these insights, our institutional protocol [ 13 ] adopts a triple‐strategy approach in the setting of a standardized clinical pathway: Induction therapy—Basiliximab with corticosteroids to blunt initial alloimmune activation. Start of Tacrolimus and MMF on pod 1. Early conversion—rapid switch from mycophenolate mofetil to sirolimus between pod 10–20 [ 15 , 16 , 17 , 27 ], combined with minimized tacrolimus exposure. Rigorous monitoring—daily TDM for both tacrolimus and sirolimus during the early postoperative phase to maintain therapeutic levels. Using this structured perioperative strategy, our cohort achieved 0% AR incidence, even among patients with short ICI washout periods (< 30 days). These results strongly suggest that AR following ICI exposure is not inevitable and can be mitigated through standardized IS regimens and close pharmacologic oversight in terms of TDM monitoring. Interestingly, these findings align with preclinical studies showing that tacrolimus combined with anti‐PD‐1 blockade can suppress tumor growth and dampen alloreactivity [ 30 ]. This study is limited by its single‐center, retrospective design, which restricts the generalizability of the findings, particularly regarding the secondary endpoints of overall OS and RFS. The sample size was relatively small, especially in the Targeted Therapy Group (2) ( n = 6) and ICI‐exposed Group (3) ( n = 13). Variable washout intervals between ICI therapy and LT introduce potential confounders that cannot be fully controlled. Furthermore, the criteria and attitudes toward selecting patients with HCC for LT have evolved since the introduction of ICI therapy. With successful downstaging, patients who were initially outside the Milan criteria are now being considered for transplantation, provided that downstaging is achieved. Consequently, the ICI‐treated cohort often includes patients with a higher initial tumor burden, which may influence outcomes and would make a direct outcome comparison not meaningful. Longer follow‐up and multicenter prospective studies, including monitoring for DSA pre‐ and posttransplant, are needed to validate these findings and to establish standardized management protocols. A key strength of our approach is the daily review of diagnostic and clinical parameters in the electronic patient record, combined with structured decision‐making during morning rounds. Given the unique clinical context of liver transplant recipients—particularly their immunosuppressed status and increased susceptibility to infections—prompt and well‐coordinated diagnostic decisions are essential. As the overall incidence of AR has declined to below 8% under modern immunosuppressive regimens, the primary clinical focus has shifted toward the early identification and management of surgical and infectious complications. This framework is reinforced by SOPs that establish standardized management and perioperative protocols (for ERAS) to systematically detect process weaknesses and enhance overall patient management. Moreover, does our study clearly indicate that survival, e.g., in the ICI group, is solely related to the initial tumor burden and not to the incidence of ARs. This group exhibited more advanced disease features in terms of tumor burden, including higher AFP levels, larger tumors, and a greater proportion of patients outside Milan criteria. While immunologic considerations are central to post‐LT outcomes, current ERAS guidelines for LT focus primarily on hemodynamic stability, analgesia, early mobilization, and nutritional optimization [ 10 ]. They offer little to no guidance on IS regimen selection, immune risk stratification, or standardized monitoring. This omission is problematic for ICI‐exposed recipients, where early postoperative abnormalities—such as liver enzyme elevation—may signal rejection, ischemia‐reperfusion injury, infection, or drug toxicity. Without protocolized immune monitoring, clinicians risk misinterpretation, leading to delays in treatment or unnecessary IS escalation. In contrast, the ERAS model described by Yuan et al. [ 13 ] integrates strict IS monitoring into a fast‐track recovery program, achieving 0% AR in their cohort—a key differentiator from traditional ERAS protocols. To improve outcomes in this complex patient population, perioperative strategies should be implemented within standardized management pathways, including harmonized immunosuppression protocols for ICI‐exposed liver transplant recipients covering induction, maintenance, and conversion strategies as well as TDM. The development of multicenter registries capturing ICI exposure, washout intervals, immunosuppression regimens, rejection grading, complications, and oncologic outcomes is essential, alongside the incorporation of transplant‐specific immune metrics into quality platforms such as the National Surgical Quality Improvement Program (NSQIP) risk score [ 31 , 32 ] to enable benchmarking and continuous improvement. Safe ICI washout intervals, which currently vary widely across studies, should be clarified through prospective research. Furthermore, publications should mandatorily report center‐specific SOPs and ERAS protocols, and multicenter studies should require shared SOPs, ERAS pathways, and uniform inclusion and exclusion criteria to ensure comparability and data validity. From a quality management perspective, transplant centers should be required to provide transparent information on their perioperative strategies—including ERAS protocols, immunosuppressive regimens, and TDM. Without such fundamental data, any conclusions regarding outcomes, such as an increased incidence of AR following ICI therapy, lack validity and hinder the identification of deficiencies in patient management. 5. Conclusion ICIs have transformed the management of HCC by allowing more patients to become eligible for LT. However, they introduce immunological complexities that cannot be addressed through conventional perioperative pathways alone. Contrary to published reports suggesting an increased risk of AR—often lacking details on immunosuppressive regimens or drug exposure (TDM)—our institutional experience indicates that the AR risk can be effectively minimized applying a standardized management pathway with an IS regimen using basiliximab induction, early mTOR inhibitor conversion, reduced tacrolimus exposure, and strict TDM within the framework of formal SOPs and an ERAS protocol. ERAS guidelines should integrate standardized immunosuppressive protocols and monitoring practices, while quality assurance systems such as NSQIP should be expanded to include transplant‐specific immunologic metrics. International, prospective collaborations applying uniform management pathways and perioperative strategies are vital to generate robust evidence and to establish globally harmonized standards for caring for ICI‐exposed liver transplant recipients in the future. Author Contributions Ning Wang: data curation (lead), validation (lead), formal analysis (lead), investigation (lead), methodology (lead), software (lead), resources (lead). Zebin Zhu: data curation (supporting). Hao Zheng: data curation (supporting). Can Qi: data curation (supporting). Xiaodong Yuan: data curation (supporting). Xuefeng Li: data curation (supporting). Zhijun Xu: data curation (supporting). Jiwei Qin: data curation (supporting). Wei Wu: data curation (supporting). Jizhou Wang: data curation (supporting). Ruipeng Song: data curation (supporting). Zhiyong Guo: writing – review and editing (supporting), methodology (supporting). Lianxin Liu: data curation (supporting). Shu‐Geng Zhang: data curation (lead), validation (lead), funding acquisition (lead). Björn Nashan: conceptualization (lead), writing – original draft (lead), writing – review and editing (lead), supervision (lead), investigation (lead), methodology (lead), project administration (lead), resources (lead). Ethics Statement The study protocol was approved by the ethics committee of First Affiliated Hospital, University of Science and Technology of China (# 2025‐RE‐229). The study was conducted in accordance with the ethical guidelines of the World Medical Association's 2013 World Declaration of Helsinki. Consent All participants provided written informed consent at the time of entering this study. Conflicts of Interest Professor Björn Nashan is a member of the Health Care Science Editorial Board. To minimize bias, he was excluded from all editorial decision‐making related to the acceptance of this article for publication. The remaining authors declare no conflicts of interest. Acknowledgments The authors have nothing to report. Contributor Information Shu‐Geng Zhang, Email: zsg0517@ustc.edu.cn. Björn Nashan, Email: bjoern.nashan@gmail.com. Data Availability Statement All data generated or analyzed during this study are included in this published article. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. References 1. Arnold M., Abnet C. C., Neale R. E., et al., “Global Burden of 5 Major Types of Gastrointestinal Cancer,” Gastroenterology 159, no. 1 (2020): 335–349.e15, 10.1053/j.gastro.2020.02.068. 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[ DOI ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Data Availability Statement All data generated or analyzed during this study are included in this published article. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. 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