Abstract
Background/Objectives: Hepatocellular carcinoma (HCC) frequently develops in the set-ting of chronic liver disease, and liver transplantation (LT) represents the most effective curative option for selected patients. Despite advances in patient selection and surveillance, HCC recurrence after LT remains a major cause of post-transplant mortality and is associated with limited therapeutic options. Immune checkpoint inhibitors (ICIs) have transformed the management of advanced HCC in non-transplant populations; however, their role after liver transplantation remains controversial due to safety concerns and the risk of allograft rejection. This narrative review aims to critically evaluate the current evidence on immunotherapy for recurrent HCC after liver transplantation. Methods: A structured narrative review of PubMed/MEDLINE was conducted through 31 May 2026. Primary clinical reports describing ICI treatment for recurrent HCC after LT were selected using predefined eligibility criteria. Results: Twenty-one primary publications were included, consisting predominantly of case reports and small case series, supplemented by three retrospective cohorts. The reports described heterogeneous oncological outcomes, including occasional durable responses, but progressive disease remained common. Allograft rejection was an important safety concern and was sometimes associated with graft failure and death. More favourable outcomes were observed among some recipients treated at longer intervals after LT; however, this pattern remains hypothesis-generating and may reflect selection and survivor bias, tumour biology, graft stability, and differences in maintenance immunosuppression. Conclusions: ICI treatment for recurrent HCC after LT is associated with uncertain oncological benefit and a clinically important risk of allograft rejection. Its use should be restricted to highly selected recipients following multidisciplinary assessment and, whenever possible, within prospective studies or structured registries.
1. Introduction
Hepatocellular carcinoma (HCC) most commonly develops in the setting of chronic liver disease, making therapeutic strategies highly dependent on both tumor burden and underlying hepatic function. Liver transplantation (LT) offers a unique oncologic advantage by achieving complete tumor removal together with restoration of liver function and remains a curative option for carefully selected patients, including selected cases beyond conventional criteria or after successful downstaging [1,2].
Despite advances in patient selection and surveillance, HCC recurrence after LT remains a major cause of post-transplant mortality and is associated with a poor prognosis, with median survival rarely exceeding one year following recurrence [3]. The risk and clinical course of recurrence are influenced by tumor-related factors, timing and pattern of relapse, and the post-transplant immunologic environment, including the type and intensity of immunosuppressive therapy [4,5]. Prognostic models such as the RETREAT score have improved risk stratification and post-transplant surveillance, yet effective therapeutic options for patients with recurrent disease remain limited [6].
In parallel, immunotherapy has transformed the systemic treatment landscape of advanced HCC in non-transplant populations. Immune checkpoint inhibitors (ICIs), particularly in combination regimens, have demonstrated superior survival outcomes compared with tyrosine kinase inhibitors and are now recommended as first-line therapy for advanced-stage disease in contemporary guidelines [1,7,8]. These agents enhance antitumor immunity by disrupting inhibitory immune signaling pathways and restoring T-cell–mediated tumor control [9].
However, extending immunotherapy to LT recipients with recurrent HCC remains highly controversial. While ICIs may provide oncologic benefit, their immune-activating mechanisms pose a significant risk of allograft rejection, potentially leading to graft loss and death. At the same time, chronic immunosuppression may attenuate ICI efficacy, creating a delicate and clinically unresolved balance between immune activation and graft tolerance [10]. Consequently, current clinical guidelines do not recommend the routine use of ICIs in patients with recurrent HCC after LT due to limited evidence and safety concerns [11].
This narrative review critically summarizes the available clinical evidence on immunotherapy for hepatocellular carcinoma recurrence after liver transplantation, focusing on reported outcomes, safety concerns, and key determinants of response. By highlighting current limitations and knowledge gaps, this review aims to contextualize immunotherapy within the broader challenges of post-transplant HCC management and to outline future research priorities.
2. Materials and Methods
2.1. Literature Search Strategy
A structured narrative review was conducted to identify primary clinical reports on the use of immune checkpoint inhibitors (ICIs) for recurrent hepatocellular carcinoma (HCC) after liver transplantation (LT). PubMed/MEDLINE was searched from 1 January 1965 to 31 May 2026 using Medical Subject Headings (MeSH) and free-text terms related to HCC, liver transplantation, and immunotherapy. The complete search strategy and the number of records retrieved at each step are provided in Supplementary Table S1.
Reference lists of eligible primary studies and relevant review articles were manually screened to identify additional potentially eligible reports. Reviews were used for contextual interpretation and citation searching but were not included as primary evidence.
2.2. Eligibility Criteria
English-language case reports, case series, and observational studies reporting ICI treatment for recurrent HCC after LT were eligible. Studies were required to provide clinical information on treatment and at least one relevant outcome, including oncological response, allograft rejection, other immune-related adverse events, graft outcome, or survival.
Studies were excluded if they evaluated ICIs exclusively before LT; reported post-transplant ICI use exclusively for malignancies other than recurrent HCC; did not involve an ICI intervention; lacked sufficient clinical information; were preclinical or non-human studies; or were reviews or other non-primary publications.
Mixed-indication studies were eligible when the number of recipients treated for recurrent HCC could be identified and the publication provided clinically relevant cohort-level safety or treatment data. Only recipients with recurrent HCC were counted as HCC patient entries. Outcomes reported exclusively for the overall mixed cohort were presented descriptively and were not interpreted as HCC-specific estimates.
2.3. Study Selection
Records were imported into Mendeley (Elsevier, Amsterdam, The Netherlands), and two reviewers (SN and SV) independently screened titles and abstracts and subsequently assessed potentially eligible full-text reports. Disagreements were planned to be resolved through discussion or consultation with a third reviewer; no third-reviewer adjudication was required.
The database search identified 1588 records. No duplicate records were identified; therefore, all 1588 records underwent title and abstract screening. Of these, 1555 were excluded, and 33 full-text reports were assessed for eligibility. Twelve full-text reports were excluded for the reasons detailed in Supplementary Table S2, and 21 primary publications were included in the qualitative synthesis.
2.4. Data Extraction and Synthesis
Extracted variables included study design, number of reported patients, ICI-based regimen, interval from LT to ICI initiation, maintenance immunosuppression, allograft rejection, other hepatic immune-mediated adverse events, oncological response, vital status, and survival after ICI initiation. Allograft rejection was distinguished from immune-mediated hepatitis and other hepatic toxicities unless rejection was explicitly diagnosed using histological or clearly stated clinical criteria.
Previous reviews were treated as secondary sources, and their patient populations were not added to those of the primary studies.
Because of the narrative design and the substantial heterogeneity of the available evidence, findings were synthesized qualitatively without meta-analysis, pooled effect estimates, or formal risk-of-bias assessment.
3. Summary of Clinical Evidence
The literature search identified 21 primary publications, including 12 case reports, six case series, and three retrospective cohort studies. Collectively, these publications accounted for 77 reported HCC patient entries. However, this number should not be interpreted as 77 unique recipients, because potential overlap between individual case reports, case series, and subsequently published cohorts could not be reliably excluded. In addition, HCC-specific outcomes were not reported separately in some mixed-indication cohorts. Accordingly, findings are presented at the study and cohort levels, and no pooled estimate of unique recipients, treatment response, rejection, or survival was calculated [12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32] (Table 1).
Table 1.
Characteristics and clinical outcomes of primary studies reporting ICI-based treatment for recurrent HCC after LT.
3.1. Study Characteristics and Patient Population
Most of the included publications were single-patient case reports or small case series including two to five recipients. Three retrospective studies were also identified: the mixed primary-liver-cancer cohort reported by Yao et al., the seven-patient HCC cohort reported by Giudicelli et al., and the multicentre mixed-indication cohort reported by De Martin et al., which included 32 recipients treated for recurrent HCC among 52 LT recipients. The reported interval between LT and ICI initiation varied substantially. Most recipients were receiving calcineurin inhibitor-based maintenance immunosuppression at ICI initiation, either alone or in combination with MMF, corticosteroids, or an mTOR inhibitor. However, immunosuppressive regimens and subsequent treatment modifications were inconsistently reported across studies [13,17,24,27,30,31,32].
3.2. Type of Immunotherapy Administered
PD-1 inhibitors were the most frequently administered ICIs, with nivolumab and pembrolizumab accounting for most of the early published experience [13,14,17,18,19,24,26]. Ipilimumab, a CTLA-4 inhibitor, was reported in a single recipient who achieved a durable complete response [25]. Pembrolizumab was administered with sorafenib in one case [20]. More recent publications evaluated atezolizumab-based treatment, including its combination with bevacizumab [28,29,30,31]. Four publications provided identifiable HCC-specific patient numbers for atezolizumab-based treatment, accounting for 16 reported HCC patient entries [28,29,30,31]. The mixed-indication cohort reported by De Martin et al. included additional ICI-treated HCC recipients, but the individual ICI regimens were not reported separately for the HCC subgroup [32]. Treatment schedules were generally based on regimens used in non-transplant populations, although treatment duration, dose modifications, and subsequent treatment were inconsistently reported.
3.3. Oncologic Outcomes
Reported oncologic outcomes were heterogeneous and were not available for all recipients. Progressive disease was the most frequently reported oncological outcome, particularly in the larger case series and the HCC-specific retrospective cohort [13,16,17,21,24,26,27,28,29,31]. Nevertheless, complete responses were documented in a small number of highly selected recipients treated with nivolumab, pembrolizumab, or ipilimumab, with some patients remaining alive for more than 24 months after ICI initiation [15,20,22,25]. Stable disease was reported less frequently [27].
These observations should be interpreted cautiously because the predominance of isolated case reports, inconsistent response-assessment criteria, incomplete follow-up, and potential publication bias preclude reliable estimation of objective response rates or comparisons among individual ICI agents.
Two HCC-focused retrospective studies provided additional cohort-level evidence regarding atezolizumab-based treatment after LT. Yao et al. [30] evaluated eight LT recipients with recurrent primary liver cancer, including six patients with HCC and two with intrahepatic cholangiocarcinoma. In the overall mixed cohort, allograft rejection occurred in two of eight recipients, median overall survival after atezolizumab initiation was 6.2 months, and six patients died during follow-up. Among seven response-evaluable recipients, the objective response rate was 28.5% and the disease-control rate was 42.9%. Because these outcomes were not reported separately for the HCC subgroup, they should not be interpreted as HCC-specific estimates. Giudicelli et al. [31] reported seven recipients treated for recurrent HCC, of whom five experienced progressive disease. These studies provide relevant cohort-level evidence, although their small sample sizes, retrospective designs, mixed or highly selected populations, and incomplete HCC-specific reporting preclude definitive conclusions regarding efficacy.
3.4. Allograft Rejection and Safety
Allograft rejection was reported following treatment with different ICIs and under various background immunosuppressive regimens. When timing was available, rejection generally occurred early after ICI initiation and, in some cases, after a single treatment dose [14,17,18,19,21]. Several reported episodes resulted in graft failure and death despite intensified immunosuppressive treatment, although non-fatal rejection was also described [14,18,19]. In the mixed cohort reported by Yao et al. [30], allograft rejection occurred in two of eight recipients; however, rejection outcomes were not reported separately for the six-patient HCC subgroup. Giudicelli et al. [31] reported allograft rejection in one of seven recipients. These findings provide relevant cohort-level observations but do not permit reliable estimation or comparison of HCC-specific rejection risk.
The diagnostic criteria for rejection were not consistently reported. Some publications documented histologically confirmed allograft rejection, whereas others described clinically suspected rejection or hepatic dysfunction without sufficient histological information. These events were therefore not considered diagnostically equivalent.
Other hepatic immune-mediated adverse events, including immune-mediated hepatitis and cholestatic liver injury, were considered separately from allograft rejection. Immune-mediated hepatitis was not classified as confirmed rejection unless the original publication explicitly reported allograft rejection based on histological or clearly defined clinical criteria. Because of heterogeneous definitions and incomplete reporting, a pooled incidence of allograft rejection was not calculated [12,23].
3.5. Survival Outcomes
Survival after ICI initiation was generally limited, with many reported recipients dying within a few months of treatment. Reported causes of death included progressive malignancy, graft failure following rejection, liver failure without clearly documented rejection, or a combination of these factors. Conversely, longer survival was reported in a small number of recipients who achieved a complete or durable tumour response without subsequent graft rejection [15,20,22,25].
Some favourable outcomes occurred in recipients who initiated ICI therapy several years after LT [15,20,22,25]. However, the available evidence does not establish that a longer interval between LT and ICI initiation independently reduces rejection risk or improves survival. The observed relationship may be influenced by selection and survivor bias, tumour biology, recipient clinical stability, background immunosuppression, and changes in transplant management over time. It should therefore be regarded as hypothesis-generating rather than clinically validated.
4. Discussion
The survival benefits achieved with ICIs in advanced HCC have not been established in recipients treated for post-LT recurrence. Pivotal registration trials evaluating ICIs in advanced HCC excluded solid-organ transplant recipients, leaving the evidence in this setting derived predominantly from case reports and small case series, supplemented by a limited number of retrospective cohorts. Consequently, conclusions regarding efficacy and safety remain tentative and highly susceptible to selection, survivor, reporting, and publication bias.
Recent narrative reviews have further highlighted the complexity of managing HCC recurrence after liver transplantation and the lack of robust evidence supporting immunotherapy in this setting. Contemporary analyses emphasize that recurrence risk, tumor biology, and post-transplant immune tolerance are tightly interconnected and require individualized therapeutic strategies rather than uniform treatment algorithms [33,34]. These reviews consistently conclude that immunotherapy after liver transplantation remains investigational and should be considered only in highly selected cases.
An updated systematic review by Dituri et al. identified 26 post-LT studies reporting 117 recipients treated with ICIs for recurrent HCC. At least 22 rejection episodes were described, generally occurring within two to four weeks after ICI initiation. However, this population substantially overlaps with the primary reports included in the present review and was therefore treated as secondary evidence rather than as an additional independent cohort. Its patient population was not added to the cumulative number of HCC patient entries [35].
4.1. Timing of Immunotherapy After Transplantation
The interval between LT and ICI initiation has been proposed as a potential modifier of treatment safety and efficacy. In the published reports, rejection appeared to occur more frequently among some recipients treated relatively early after LT, whereas several favourable outcomes were reported in recipients who initiated ICI therapy years after transplantation. Furthermore, all complete responses identified in the present evidence set occurred in recipients who received ICIs at least one year after LT. These observations may suggest a possible relationship between a longer LT-to-ICI interval and more favourable outcomes; however, they should be regarded as hypothesis-generating rather than evidence of an independent or causal effect [15,20,22,24,25,35,36,37,38,39].
Several alternative explanations may account for the observed pattern. Recipients surviving long enough to receive ICIs several years after LT represent a selected population with established graft stability and potentially more favourable clinical characteristics. Late HCC recurrence may also reflect less aggressive tumour biology, while patients with early recurrence may have more rapidly progressive disease and a poorer prognosis irrespective of ICI treatment. In addition, the intensity and composition of maintenance immunosuppression, previous rejection episodes, recipient comorbidities, oncological treatment history, and transplant-management practices may differ substantially according to the time elapsed since LT.
The available evidence is derived predominantly from selected case reports, small case series, and retrospective cohorts and is therefore particularly vulnerable to survivor, selection, and publication bias. Consequently, no clinically validated minimum interval between LT and ICI initiation can be defined. The LT-to-ICI interval should not be used in isolation to determine treatment eligibility but may be considered as one component of an individualized multidisciplinary risk assessment.
4.2. Immunosuppression Modulation and Rejection Risk
The interaction between ICIs and background immunosuppression remains poorly understood. Modifications of immunosuppressive regimens at the time of cancer diagnosis or during immunotherapy appear to influence both rejection risk and oncologic outcomes, though available evidence is inconsistent. Some reports observed an absence of rejection among recipients who continued tacrolimus-based immunosuppression, whereas rejection was described following substantial immunosuppression reduction in other cases. However, these observations are uncontrolled and do not establish a protective effect of tacrolimus or a causal relationship between immunosuppression modification and rejection [21,24]. n the De Martin cohort, calcineurin inhibitor use and intensification of immunosuppression at ICI initiation were associated with a lower observed rejection risk; however, the retrospective design precludes causal inference [32]. Conversely, favorable outcomes without rejection have been reported with diverse strategies, including tacrolimus dose reduction, mTOR inhibitor addition, or even increased calcineurin inhibitor exposure [16,20,25].
Recent expert reviews emphasize that immunosuppression should not be viewed as a static background therapy but as a dynamic variable that may critically influence immunotherapy outcomes. Integrated strategies combining immunosuppressive modulation with oncologic treatment—rather than abrupt reduction or withdrawal—have been proposed to mitigate rejection risk while maintaining graft tolerance, although these approaches remain largely theoretical and unvalidated [36,38].
In the largest retrospective cohort included in the present review, De Martin et al. reported a multicentre retrospective cohort of 52 LT recipients treated with ICIs for either HCC recurrence or de novo malignancy. Allograft rejection occurred in seven recipients (13%), at a median of 27 days after ICI initiation. Calcineurin inhibitor use and intensification of immunosuppression at ICI initiation were associated with a lower observed risk of rejection. However, the mixed oncological indications and retrospective non-randomized design limit HCC-specific interpretation and preclude causal conclusions regarding the protective effect of individual immunosuppressive strategies [32].
4.3. Acute Rejection: Clinical Course and Management
Acute allograft rejection remains the most feared complication of immunotherapy after LT and can be rapidly fatal. Most reported cases occurred early after ICI exposure, sometimes after a single dose, and were frequently refractory to high-dose corticosteroids and additional immunosuppressive interventions [14,18]. Although isolated cases of reversible rejection have been described [19], outcomes remain unpredictable, and mortality is high, highlighting the limited capacity to rescue graft function once immune activation is triggered.
4.4. Type of Immunotherapy and Mechanistic Considerations
Most published experience involves PD-1 inhibitors, particularly nivolumab and pembrolizumab, reflecting their established efficacy in non-transplant HCC. CTLA-4 inhibition has been reported less frequently and may theoretically confer a lower rejection risk; however, the small number of reported cases precludes firm conclusions. The PD-1/PD-L1 pathway plays a central role in graft tolerance, and disruption of this axis likely underlies the high rejection rates observed. Assessment of graft PD-L1 expression has been proposed as a potential biomarker of rejection risk, although its clinical utility remains unproven and highly context-dependent.
Beyond immune checkpoint blockade, emerging immunotherapeutic approach-es—including cellular-based strategies—have been proposed as potential alternatives in the transplant population. Recent reviews suggest that adoptive cell therapies may theoretically offer antitumor activity with a different immune activation profile com-pared with ICIs, although clinical experience remains extremely limited [40]. At present, such approaches should be confined to research settings.
4.5. Immune-Related Adverse Events Beyond Rejection
In addition to rejection, immune-related adverse events such as hepatitis or colitis may substantially contribute to morbidity and mortality. Management in transplant recipients is particularly challenging, as steroid-refractory immune toxicity may coexist with baseline immunosuppression and underlying graft vulnerability. Severe immune-mediated liver injury has been reported, underscoring the need for alternative therapeutic strategies in steroid-resistant cases [12,23,41].
4.6. Limitations of the Available Evidence
The current literature is characterized by small, heterogeneous cohorts, variable immunosuppressive regimens, inconsistent ICI dosing and sequencing, and incomplete reporting of comorbidities and long-term outcomes. These limitations preclude meaningful comparisons and reinforce the need for prospective, collaborative studies.
Overall, the available reviews and primary studies indicate that ICI treatment for recurrent HCC after LT remains a high-risk intervention with uncertain oncological benefit. Apparent associations between favourable outcomes and factors such as a longer LT-to-ICI interval or specific immunosuppressive strategies remain exploratory and may be explained by selection and survivor bias, tumour biology, graft stability, differences in maintenance immunosuppression, and evolving transplant practices. Current evidence therefore supports only a highly selective and individualized approach and highlights the need for prospective multicentre research before broader adoption can be considered [32,34,38,42].
5. Conclusions
HCC recurrence after LT remains a major clinical challenge associated with limited effective treatment options and poor prognosis. Although ICIs have transformed the management of advanced HCC in non-transplant populations, their use in LT recipients with recurrent disease is constrained by the risk of allograft rejection and highly variable oncological outcomes. Current evidence, derived predominantly from case reports and small case series and supplemented by limited retrospective cohort data, suggests that durable responses may occur in selected recipients. However, the likelihood of benefit cannot currently be predicted reliably and must be balanced against the potential for severe or fatal graft injury.
A longer interval between LT and ICI initiation has been associated with favourable outcomes in some published reports. Nevertheless, this observation remains hypothesis-generating and may reflect selection and survivor bias, less aggressive tumour biology, greater graft stability, differences in maintenance immunosuppression, and changes in transplant management over time. No specific LT-to-ICI interval has been clinically validated as a threshold for safe treatment.
At present, ICI therapy for recurrent HCC after LT should be considered only in highly selected recipients following multidisciplinary assessment and, whenever feasible, within prospective studies or structured registries. Future research should focus on identifying predictive biomarkers of tumour response and rejection, clarifying the influence of maintenance immunosuppression, and developing safer, individualized treatment strategies. Until more robust evidence becomes available, routine ICI use in this high-risk population cannot be recommended.
Supplementary Materials
The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/transplantology7030020/s1: Table S1. PubMed/MEDLINE search strategy. Table S2. Full-text reports excluded after eligibility assessment.
Author Contributions
Conceptualization, S.V. and N.A.; methodology, S.V. and S.N.; investigation, S.V., S.N., F.F.K., A.K. and I.P.; data curation, S.V., A.K. and I.P.; writing—original draft preparation, S.V.; writing—review and editing, S.V., S.N., F.F.K., N.A., E.S. and G.T.; supervision, G.T. and E.S. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript:
| HCC | Hepatocellular carcinoma |
| LT | Liver transplantation |
| ICI(s) | Immune checkpoint inhibitors |
| PD-1 | Programmed cell death protein 1 |
| PD-L1 | Programmed death-ligand 1 |
| CTLA-4 | Cytotoxic T-lymphocyte-associated protein 4 |
| OS | Overall survival |
| mTOR | Mechanistic target of rapamycin |
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