ABSTRACT
Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and hepatocellular carcinoma (HCC). Advances in surgical techniques and immunosuppressive regimens have markedly improved early post-transplant survival. However, long-term outcomes remain compromised by HCC recurrence, chronic rejection, metabolic complications, and de novo malignancies. Recurrence of HCC after LT remains a major clinical challenge, with available prognostic models providing limited accuracy in risk stratification. Simultaneously, systemic therapies for unresectable HCC have rapidly advanced, particularly with immune checkpoint inhibitors (ICIs), providing new opportunities and unique challenges in transplant settings. With ICIs carrying a risk of acute and potentially fatal rejection and lacking controlled data on efficacy or safety in the post-transplant setting, tyrosine kinase inhibitors currently represent a standard option for post-transplant recurrence. Novel biomarkers, such as donor-derived cell-free DNA and the gut microbiome, are emerging as potential tools to refine risk stratification and guide immunosuppression. Furthermore, innovative immunotherapies, including oncolytic viruses and mRNA vaccines, are being explored as tumor-specific approaches. Collectively, these advances may reshape future management of LT recipients.
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Keywords: Liver transplantation; Hepatocellular carcinoma; Immune checkpoint inhibitors; Immunosuppressive therapy; Graft rejection
INTRODUCTION
Liver transplantation (LT) is the standard treatment for end-stage liver disease and selected hepatocellular carcinoma (HCC), with curative potential when other approaches are inadequate [
1]. Since the first clinical success >5 decades ago, advances in surgical techniques, perioperative management, and immunosuppressive therapy have transformed LT into an established clinical practice with 1-year survival rates approximately 90% and mean estimated survival extending to approximately 20 years in recipients who underwent transplantation in the 1990s [
2]. The introduction of calcineurin inhibitors (CNIs) marked a turning point, substantially improving graft survival, whereas subsequent refinements with mechanistic target of rapamycin (mTOR) inhibitors and antimetabolites have further optimized outcomes [
3-
6]. Despite these achievements, critical challenges remain unsolved. Long-term survival is threatened by chronic rejection, metabolic complications, infections, and malignancies. Of these factors, recurrent HCC is a major concern. Recurrence rates after LT are between 8–20%, and are strongly affected by tumor burden, vascular invasion, and biological aggressiveness [
7]. Various selection criteria, including the Milan and University of California San Francisco (UCSF) criteria, have been proposed to reduce recurrence and identify patients who are most likely to benefit from transplantation [
8,
9]. For patients whose initial tumor burden exceeds these conventional criteria, downstaging-the use of locoregional therapies (LRTs) to reduce tumor size and number to meet transplant eligibility—has become an essential strategy. Common methods for downstaging include transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and yttrium-90 radioembolization [
10]. A prospective multicenter study demonstrated successful downstaging rates exceeding 80%, with 2-year post-LT survival of 95% [
11]. To better select candidates and predict post-transplant outcomes, biological markers are increasingly integrated into selection models. Key examples include the AFP model and the Metroticket 2.0 criteria, the latter of which predicts survival by integrating tumor size, number, and AFP levels as continuous variables [
12,
13]. Importantly, despite favorable outcomes among patients successfully downstaged to within Milan criteria, post-LT recurrence rates remain higher in this population (approximately 12–13%) compared with those initially within Milan criteria (approximately 7%) [
14,
15]. Although these strategies have improved patient selection, recurrence still occurs in a significant subset, underscoring the need for refined prognostication and effective post-transplant surveillance [
13,
16,
17].
In recent years, systemic therapy for unresectable HCC (uHCC) has progressed markedly, shifting from tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, to the widespread use of immune checkpoint inhibitors (ICIs) and combination regimens, altering the therapeutic landscape [
18-
22]. However, for patients with recurred HCC after LT, TKIs are the standard of care due to the risk of graft rejection associated with ICIs. Sorafenib has long been the mainstay of treatment among TKIs. However, lenvatinib has recently emerged as a key therapeutic option [
23]. It offers potentially superior survival benefits compared to sorafenib, with a safety profile comparable to that observed in non-transplant populations. Given the high efficacy of ICIs in uHCC, these advances underscore a major clinical dilemma: ICI administration at the time of HCC recurrence can increase the risk of graft rejection; however, effective cancer control remains essential. Additional considerations include the adjustment of immunosuppressive therapy and appropriate timing for ICI administration.
In this review, we provided an overview of immunosuppressive agents relevant to LT and discussed their relationship with HCC recurrence. We then addressed the use of ICIs in liver transplant recipients, both in post- and pretransplant settings. Finally, we explored future perspectives, including strategies for refining recurrence risk stratification and the potential of novel immunotherapeutic approaches.
IMMUNOSUPPRESSION IN LT
LT was first reported in 1963 by Dr. Thomas Starzl; however, its adoption has not expanded because of poor prognosis associated with rejection [
1,
24]. In the 1980s, cyclosporine therapy became widespread, which markedly reduced the incidence of rejection and improved patient outcomes, leading to an increase in the number of LTs [
25]. Today, immunosuppressive therapies remain central to post-LT management, along with improvements in surgical techniques, infection control, and rejection treatment. As a result of these advancements, survival after LT has improved significantly, with 1-year survival now approximately 90% and 5-year survival exceeding 75% in many institutions in the United States and Europe, respectively. In patients with HCC, careful selection based on criteria, such as the Milan or UCSF guidelines, has yielded posttransplant outcomes comparable with those observed in patients without cancer [
2].
As the liver is continuously exposed to gut-derived antigens, it maintains a tolerogenic immune environment characterized by tolerogenic antigen-presenting cells (APCs) and Kupffer cells, partly through the production of interleukin-10 (IL-10) and prostaglandin E2 [
26]. As a result, liver transplant recipients require lower levels of immunosuppression than recipients of other organ transplants such as the kidney or heart. Although the liver is immunologically tolerant, graft failure occurs in approximately 20% of recipients within 5 years, highlighting the importance of maintaining immunosuppressive therapy to prevent rejection [
27].
Post-transplant immunosuppression is typically divided into three phases: induction, maintenance, and rejection. In LT, induction therapy most commonly consists of perioperative high-dose intravenous corticosteroid boluses, followed by early conversion to oral therapy and rapid tapering, together with early initiation of tacrolimus-based immunosuppression [
28-
30]. Tacrolimus is typically started soon after transplantation; in a prospective cohort study, an initial dose of approximately 0.1 mg/kg/day was used, and early trough concentrations of 7–10 ng/mL during the first two weeks were sufficient to prevent acute rejection while minimizing toxicity [
31]. During the maintenance phase, immunosuppressive intensity is gradually reduced, with tacrolimusbased therapy forming the backbone of long-term management. Corticosteroids are tapered and discontinued, while tacrolimus dosing is adjusted using therapeutic drug monitoring, with lower trough levels of approximately 3–8 ng/mL commonly targeted in clinically stable recipients to minimize long-term complications [
30]. Episodes of rejection represent a distinct phase requiring temporary escalation of immunosuppression, most commonly with corticosteroids. These immunosuppressive strategies employ several drug classes that target different stages of the immune cascade (
Table 1). Corticosteroids are used for both induction and rejection treatment, although long-term use carries metabolic and infectious risks [
6,
32]. CNIs, particularly tacrolimus, remain the key component of maintenance regimens due to their superior efficacy in preventing graft loss, despite the ongoing challenge of nephrotoxicity [
33,
34]. Antimetabolites (e.g., mycophenolate mofetil [MMF]) and mTOR inhibitors provide adjunctive immunosuppression and allow CNI dose reduction to preserve renal function [
4,
5,
35]. Biologic agents, including antithymocyte globulin (ATG) and basiliximab, are primarily used in induction or for managing steroid-resistant rejection. In the liver transplant setting, their use is generally reserved for selected cases, such as re-transplantation, combined liver-kidney trans-plantation, or renal-sparing protocols with delayed introduction of CNIs, due to concerns regarding infectious complications [
3,
36].
MECHANISMS OF REJECTION AND TARGETS OF IMMUNOSUPPRESSION
Rejection after LT is mediated by both T cell-driven cytotoxicity and donor-specific antibody (DSA)-induced complement activation, with T cell-mediated mechanisms representing the predominant pathway in most cases. In addition to T cell-mediated rejection, antibody-mediated rejection (AMR), driven by DSAs, is an increasingly recognized but relatively uncommon form of rejection after LT [
37]. AMR is typically diagnosed based on a combination of graft dysfunction, histopathologic features such as portal microvascular injury, C4d deposition, and the presence of circulating DSAs [
37,
38]. Although the liver is relatively resistant to antibody-mediated injury compared with other solid organs, AMR has been associated with graft dysfunction and inferior outcomes in selected cases [
37,
38]. Treatment strategies are not standardized but generally include intensification of immunosuppression, plasmapheresis, intravenous immunoglobulin, and B-cell–targeted therapies such as rituximab, depending on severity and clinical context [
39].
The cascade of T cell–mediated rejection begins when donor or recipient APCs display donor-derived antigens (
Fig. 1). Donor APCs present these antigens through their human leukocyte antigen molecules to recipient T cells. Biologic agents such as ATG and alemtuzumab directly deplete T cells; however, alemtuzumab is rarely used in contemporary LT because of profound and prolonged immunosuppression and limited supporting data.
T cells that receive co-stimulatory signals internalize an antigen and activate calcineurin, which subsequently stimulates nuclear factor of activated T cells (NFAT). NFAT induces IL-2 production, a pivotal growth factor that drives T cell proliferation. CNIs suppress this calcineurin–NFAT– IL-2 axis, but because their therapeutic concentrations lie very close to the toxic range, regular monitoring of blood levels is essential to balance efficacy and safety. Additionally, CNIs are metabolized by cytochrome P450 3A4/5 (CYP3A4/5), and their clearance is easily affected by other drugs, leading to frequent drug–drug interactions. When IL-2 binds to its receptor, the downstream mTOR pathway is activated, driving clonal expansion of lymphocytes. The mTOR pathway functions as a regulatory hub for cell growth and proliferation. Inhibitors of mTOR complex 1 (mTORC1) are therefore used not only as immunosuppressants in transplantation but also as anticancer agents, as in renal cell carcinoma.
MMF and azathioprine inhibit DNA synthesis, thereby preventing lymphocyte proliferation. MMF exerts its effect with relatively higher selectivity for lymphocytes [
40]. Azathioprine acts less specifically, and is more likely to cause systemic toxicities such as bone marrow suppression. Activated T cells exert cytotoxicity by releasing perforin and granzymes while simultaneously secreting cytokines and chemokines that recruit inflammatory cells such as neutrophils and NK cells. Corticosteroids suppress inflammatory cascades through multiple mechanisms [
6,
41]. They act not only through genomic regulation of transcription but also through rapid non-genomic actions. This non-genomic mechanism explains the rapid onset of immunosuppressive effects, which is why corticosteroids are particularly effective in treating acute rejection, in which a prompt therapeutic response is required.
ONCOLOGIC EFFECT OF IMMUNOSUPPRESSIVE THERAPY
Several studies have highlighted the oncogenic potential of tacrolimus after LT, as overexposure to tacrolimus is consistently associated with an increased risk of HCC recurrence and
de novo malignancies. The potential oncogenic effect of tacrolimus was first suggested in early animal models, demonstrating its role in promoting tumor progression via transforming growth factor-beta 1 overexpression [
42]. This association was later reported in a small clinical series in 2008, where Vivarelli et al. [
43] identified high tacrolimus levels as an independent predictor of HCC recurrence after LT. Tacrolimus trough levels >10 ng/mL in the first month after LT have been linked to an increased risk of HCC recurrence [
7]. Additionally, higher average blood levels during the first year were associated with a greater incidence of solid cancers, highlighting a dose-dependent effect [
44]. Furthermore, cumulative tacrolimus exposure over time strongly correlated with a higher cancer incidence post-LT, emphasizing a dose-dependent effect [
45]. Early reduction of CNI levels after LT lowers the risk of HCC recurrence, suggesting that appropriate minimization of CNI exposure plays a key role in post-transplant management [
7].
Although mTOR inhibitors have shown anti-tumor effects in preclinical studies, their benefits in reducing HCC recurrence after LT remain unclear. Some retrospective studies and meta-analyses have suggested a potential reduction in recurrence risk with mTOR-based regimens [
46,
47]. However, no prospective trials have been conducted to date to specifically evaluate the impact of mTOR inhibitor–based regimens on HCC recurrence in liver transplant recipients. Therefore, although mTOR inhibitors may be helpful in some patients, stronger evidence is needed before they can be broadly recommended. Immunosuppressive management after LT is inherently complex, as it requires balancing graft protection with the long-term risk of malignancy. This balance is particularly relevant in patients with HCC, in whom the degree and duration of immunosuppression can critically affect the risk of tumor recurrence.
HCC RECURRENCE AFTER LT: RISK PREDICTION AND MONITORING
HCC recurrence remains a significant challenge following LT, with recurrence rates between 8–20%, depending on patients and tumor size [
8,
48-
50]. Several risk factors have been identified for post-LT HCC recurrence. Tumor-related factors, including larger tumor size and vascular invasion, are associated with a higher risk of recurrence [
16,
51,
52]. Elevated pre-transplant alpha-fetoprotein (AFP) levels are also associated with a high recurrence rate, especially levels >400 ng/mL predicting significantly worse outcomes [
13,
17]. In addition to radiologic tumor burden and serum biomarkers, explant histopathology provides critical prognostic information that refines post-LT recurrence risk. Microvascular invasion (MVI) is consistently one of the strongest predictors of recurrence, and other adverse histologic features—such as microsatellitosis and poor tumor differentiation—have also been associated with increased recurrence risk [
53].
Several prognostic models have been developed to predict the risk of recurrence. The HALT-HCC score estimates recurrence risk based on pre-transplant tumor burden and serum biomarkers, without incorporating explant histopathological findings [
54]. Several post-transplant models also incorporate pathological findings from the explanted liver to further characterize recurrence risk. The RETREAT score integrates AFP levels, MVI, and maximum viable tumor diameter on explant pathology and has been externally validated to reliably stratify recurrence risk [
55,
56]. Similarly, the new MORAL score incorporates explant pathological features, including tumor grade and vascular invasion, together with tumor burden [
57].
Post-LT surveillance for HCC recurrence should balance early detection with cost-effectiveness. The intensity and frequency of surveillance may reasonably be tailored according to the estimated risk of recurrence, as defined by clinicopathological features and validated risk prediction models. Patients classified as high risk based on factors such as advanced tumor burden, elevated AFP levels, or adverse explant pathology may benefit from closer surveillance, particularly during the early post-transplant period. AFP has proven useful in predicting recurrence, and serial AFP measurements are recommended at regular intervals [
58]. Additionally, imaging plays a critical role, especially during the first 2 years post-LT, when the risk of recurrence is highest. Evidence suggests that extending the imaging interval from every 3 months to every 6 months during the first 5 years does not significantly delay recurrence detection, while reducing radiation exposure and cost [
59]. For patients with a lower estimated risk of recurrence, less intensive surveillance strategies may be sufficient without compromising oncologic outcomes. A practical approach may involve measuring AFP and other serum markers every 1–3 months, with computed tomography or magnetic resonance imaging performed every 6 months in the absence of rising markers or symptoms.
ICIS AND LT
Advances in systemic therapy for uHCC
Over the past two decades, the therapeutic landscape for uHCC has significantly progressed. In 2008, the SHARP trial demonstrated the efficacy of sorafenib, establishing it as the first systemic therapy to improve the survival of patients with uHCC [
18]. A decade later, the REFLECT trial showed that lenvatinib was not inferior to sorafenib, making it an alternative first-line treatment option [
19]. A major paradigm shift occurred in 2020 when the IMbrave150 trial revealed that a combination of atezolizumab plus bevacizumab significantly improved overall and progression-free survival compared with sorafenib [
20]. In 2022, the HIMALAYA study introduced the STRIDE regimen (tremelimumab plus durvalumab), which achieved superior survival outcomes compared with sorafenib [
21]. In 2025, CheckMate-9DW confirmed that nivolumab plus ipilimumab improved survival over lenvatinib or sorafenib, with a 36% objective response rate and 7% complete response rate [
22]. These advances highlight two major distinctions between TKIs and ICIs: first, ICIs offer higher response rates, including complete responses that are infrequent with TKIs; second, efficacy is mediated through host immunity, resulting in immune-related adverse events. In the context of LT, the latter requires caution because of the risk of graft rejection under immunosuppression.
HCC has a high propensity for recurrence even after curative treatment, and perioperative systemic approaches have therefore been actively explored. The phase 3 STORM trial, which evaluated sorafenib after resection or ablation, showed no improvement in recurrence-free or overall survival, indicating a lack of adjuvant benefit [
60]. Several small retrospective and early-phase studies have examined postoperative lenvatinib in patients with high-risk pathological features. Although some reports suggest a potential reduction in recurrence, the available evidence is limited to small, non-randomized studies with heterogeneous designs, and does not at present establish a clear role for adjuvant lenvatinib [
61].
Adjuvant ICI therapy has also been investigated. In the phase 3 IMbrave050 trial, atezolizumab plus bevacizumab demonstrated an initial recurrence-free survival advantage; however, this benefit was not sustained with longer followup, and the regimen has not been established as a standard adjuvant strategy [
62]. Additional perioperative ICI trials continue to evaluate whether recurrence risk can be meaningfully reduced in this setting.
Neoadjuvant ICI approaches are likewise gaining interest. Early-phase studies have shown that administering ICIs before surgery can induce major pathologic responses without delaying resection and with manageable toxicities, supporting the biological rationale for preoperative immune activation [
63]. Nevertheless, current evidence for both adjuvant and neoadjuvant ICI remains preliminary, and further investigation is required to define their optimal role in managing high-risk HCC.
Since the initial approval of ICIs for melanoma in 2011, their use has been attempted in patients with prior organ transplantation. Although several reports have described transplant recipients experiencing clinical benefits from ICIs without compromising graft function, an increasing number of cases have documented acute rejection, raising concerns regarding graft loss and mortality [
64-
66].
A pharmacovigilance analysis conducted in 2020 summarized 57 transplant recipients (kidney, liver, cornea, and heart) who developed rejection at a median of 18 days after ICI initiation, with an overall mortality rate of 40%; 13 of 17 liver transplant recipients (76.5%) died following rejection [
67]. In patients with HCC recurrence after LT, a pooled review identified rejection in 6 of 23 cases, with three deaths occurring within 1 month of ICI initiation [
68].
Despite these safety concerns, ICI responsiveness varies substantially among patients, partly reflecting differences in lymphocyte composition and activity [
69]. This variability suggests that in some individuals the immunologic impact of ICIs after transplantation may also be limited. On this basis, recent studies have begun to investigate whether ICI-based combinations could be feasible in carefully selected post-transplant patients. Di Marco et al. [
70] conducted a proof-of-concept study to evaluate nivolumab combined with bevacizumab for post-transplant HCC recurrence. In their cohort, ICIs were initiated after a median of 14.5 months from transplantation (range, 4–106 months). Four patients received the ICI-based combination; one developed moderate graft rejection that was resolved with corticosteroids, while the others achieved disease stabilization with significantly longer survival than with regorafenib.
Furthermore, a review by Munker and De Toni [
71] indicated that programmed death-ligand 1 (PD-L1) expression in liver allografts may be linked to the risk of rejection. They analyzed 14 published cases of liver transplant recipients treated with ICIs and found that three patients whose grafts showed high PD-L1 expression developed acute rejection, which was fatal in most cases, whereas among four patients with PD-L1–negative grafts, none experienced rejection. Shi et al. [
72] also reported that all liver transplant recipients who developed rejection after anti–programmed cell death protein 1 (PD-1) therapy showed positive PD-L1 expression in graft biopsies, whereas none of those with PDL1– negative grafts experienced rejection, suggesting that graft PD-L1 status is a potential predictive biomarker for ICI safety.
These findings suggest that pre-treatment liver biopsy with PD-L1 staining could help identify patients at lower risk when considering ICIs after LT. In line with these observations, Yang et al. [
73] reported a liver transplant recipient with recurrent HCC who received atezolizumab plus bevacizumab after confirming negative PD-L1 staining in pretreatment liver graft biopsy; however, no graft rejection was observed. Nevertheless, it must be noted that no controlled studies have demonstrated the efficacy or safety of such treatment in the post-transplant setting. Whereas rejection after kidney or corneal transplantation may be managed with dialysis or vision loss without immediate fatality, rejection in a LT setting often results in death in the absence of a new graft. Thus, the risk of ICI administration after LT should be considered particularly high compared with other transplanted organs. Reported cases of ICI administration after LT for recurrent HCC with available clinical data are summarized in
Table 2 [
73-
85].
The use of ICIs after LT has been associated with a high risk of acute rejection because the PD-1/PD-L1 pathway is critical for maintaining graft tolerance. In murine models, PD-1 or PD-L1 inhibitors disrupt the spontaneous acceptance of liver allografts, leading to severe T cell infiltration, tissue necrosis, and graft loss. Upregulation of PD-L1 in donor parenchymal cells normally induces apoptosis of infiltrating T cells, thereby contributing to tolerance; interference with this pathway abrogates this protective mechanism [
86].
Studies among humans have confirmed the importance of this axis. In liver transplant recipients, PD-L1 is expressed in hepatocytes, cholangiocytes, and sinusoidal cells, whereas PD-1 is abundant in graft-infiltrating T cells. Blockade of PD-L1 ex vivo augments the proliferative response of these T cells, underscoring its inhibitory role [
87]. Moreover, donor and recipient PD-L1 and PD-1 polymorphisms significantly influence the risk of late acute rejection, highlighting the clinical relevance of this pathway in humans (
Fig. 2) [
87].
Complementary evidence indicates that T cell exhaustion, characterized by sustained PD-1 expression and functional impairment, can promote transplant acceptance [
88]. Thus, by reinvigorating exhausted T cells and preventing PD-1/PD-L1–mediated regulation, ICIs remove a central checkpoint of alloimmune control, resulting in rejection episodes after LT.
Given the concern of graft rejection with ICIs in the posttransplant setting, TKIs remain the mainstay for systemic therapy of recurrent HCC after LT. Sorafenib was historically the most frequently used agent, but the outcomes were heterogeneous and tolerability was often limited [
89,
90]. Recent studies have demonstrated the feasibility of lenvatinib, showing encouraging survival and manageable safety profiles, comparable with those in non-transplant populations [
23]. Retrospective analyses, including multicenter cohorts, suggest that lenvatinib may provide longer survival than sorafenib and thus represents a valuable therapeutic option for patients with HCC recurrence after transplantation [
91].
Although the administration of ICIs after LT remains associated with a high risk of graft rejection and is generally discouraged, the use of ICIs prior to LT has recently become increasingly practiced as a means of downstaging HCC within the transplant criteria [
92]. Unlike TKIs, which typically achieve modest tumor control, ICIs are characterized by higher objective response rates, thereby allowing patients with an initially extensive tumor burden to be eligible for curative LT. More recently, the concept of conversion therapy has emerged, wherein patients with initially uHCC who achieve tumor shrinkage following ICI-based systemic therapy may become candidates for curative treatment through the addition of LRTs such as resection, RFA, or selective TACE, with some patients becoming eligible for LT following successful conversion [
93].
Several studies have highlighted the potential of ICIs in this setting [
94,
95]. A representative case from Spain exemplifies this approach: a patient with multifocal HCC, including 13 lesions with a maximum diameter of 47 mm, was initially treated with sorafenib and subsequently with durvalumab (anti–PD-L1 antibody) as second-line therapy. This regimen induced marked tumor shrinkage, thereby reducing the disease burden to within accepted LT criteria. During the waiting period, TACE was performed as a bridging therapy to prevent disease progression, and LT was successfully performed. At the time of transplantation, no viable tumor tissue was identified in the explant, and the patient remained disease-free for at least 24 months after LT [
95]. In line with these advances, the 2025 European Association for the Study of the Liver clinical practice guidelines outlined specific recommendations regarding the role of downstaging in LT. The guidelines state that in patients with uHCC beyond established transplant criteria, downstaging within the framework of experimental protocols can be considered to achieve eligibility for LT. Additionally, for patients whose disease is beyond the Milan criteria but still within extended criteria, downstaging with locoregional and/or systemic therapies is recommended as a bridging strategy to LT [
96].
Although ICI administration after LT is associated with a considerable risk of allograft rejection, recent studies have investigated this risk in patients undergoing LT after ICI treatment. A systematic review and individual patient data meta-analysis, including 91 patients with HCC who underwent LT after ICI therapy, reported an allograft rejection incidence of 26%, without a significant difference in overall survival between patients with and without rejection [
97]. Furthermore, a retrospective cohort study demonstrated that the interval between the last ICI administration and LT was significantly shorter in patients who developed rejection than in those who did not (median, 21 vs. 60 days) [
98]. A study comparing different washout intervals reported that extending the interval beyond 50 days reduced the incidence of rejection to <10% [
99]. Additionally, an analysis that incorporated recipient age demonstrated that the risk of rejection decreased by 28% for every 10-year increase in age, and by 8% for each additional week of washout. In this analysis, an interval of ≥94 days was associated with an allograft rejection risk of <20% [
97]. Pharmacokinetic and immunologic considerations may help explain why rejection risk can persist beyond the immediate post-ICI period. Anti-PD-1 antibodies such as nivolumab and pembrolizumab have prolonged half-lives of approximately 25–27 days [
100]. However, their pharmacologic effects often persist far beyond their systemic clearance due to sustained occupancy of the PD-1 receptors; studies have demonstrated that receptor occupancy on T cells can remain as high as 70% even two months after the last dose [
100,
101]. Furthermore, ICIs promote the expansion of antigen-specific memory T cells, including tissue-resident memory T cells, which can persist in allografts and maintain alloreactive potential even after treatment cessation [
102,
103]. Once primed by ICIs, these long-lived memory T cell populations may contribute to delayed allograft rejection occurring weeks to months after exposure, underscoring the importance of adequate washout intervals prior to transplantation.
Although extending the washout interval can improve the safety of LT after ICI exposure, there remains a risk of tumor progression during the waiting period, potentially leading to ineligibility for transplantation. In such cases, bridging therapy with LRT may be beneficial. For example, a retrospective study demonstrated that adding TACE as a bridging LRT in patients with HCC awaiting LT significantly reduced the risk of dropping out of a waiting list within 20 months [
104]. Beyond TACE, other modalities, such as RFA and radiotherapy can also be employed, and LRT is generally expected when the anticipated waiting period exceeds six months [
105,
106]. Moreover, a study showed that in patients with tumors >30 mm, the addition of LRT prior to LT was associated with improved post-transplant survival [
107]. Taken together, consideration of tumor characteristics along with the ICI washout interval is warranted when deciding whether to incorporate bridging LRT.
Therefore, an integrated treatment strategy is essential for patients with uHCC (
Fig. 3). Systemic therapy can induce downstaging, bringing tumors within transplant criteria, whereas LRT serves as a bridging intervention to maintain tumor control and prevent waitlist dropouts. By combining these approaches sequentially, patients can remain transplant-eligible and ultimately undergo LT. This continuum, from systemic therapy through bridging to transplantation, represents a practical approach for enhancing long-term outcomes and optimizing the use of donor grafts in the ICI era [
92].
Optimal immunosuppressive management after HCC recurrence requires a delicate balance between preserving graft function and enhancing anti-tumor efficacy. At present, there is no high-level consensus regarding the optimal regimen in this setting, largely due to the absence of prospective randomized controlled trials specifically addressing immunosuppressive strategies after tumor recurrence. mTOR inhibitors have attracted interest because of their immunosuppressive and anti-proliferative properties. Importantly, evidence from the SiLVER trial pertains to patients who received sirolimus as part of their baseline immunosuppression prior to recurrence, rather than as a therapeutic intervention initiated after recurrence [
108]. In this randomized trial, sirolimus did not confer a sustained improvement in recurrence-free or overall survival in the overall cohort, although transient benefits were observed in selected low-risk patients during early follow-up.
With respect to everolimus, emerging evidence suggests potential benefit when combined with systemic therapy. Nitta et al. [
109] reported that, in a relatively small retrospective cohort, the combination of everolimus and sorafenib was an independent predictor of improved survival after HCC recurrence, with the greatest benefit observed in patients who achieved well-controlled everolimus trough levels (≥5 ng/mL). However, although acceptable tolerability was reported in this series, a prior phase I study evaluating everolimus in combination with sorafenib demonstrated substantial dose-limiting toxicities, necessitating dose reduction of everolimus to 2.5 mg/day and revealing frequent hematologic, gastrointestinal, and dermatologic adverse events [
110]. These findings indicate that this combination requires careful patient selection and close monitoring in clinical practice.
In the absence of definitive prospective evidence supporting the oncologic superiority of mTOR inhibitor-based strategies, many transplant centers currently favor a pragmatic approach consisting primarily of CNI minimization, given that excessive CNI exposure is a well-established risk factor for tumor progression after LT [
43].
The future of liver transplant care will likely integrate novel biomarkers to predict rejection and targeted therapies to manage post-transplant malignancies. Noninvasive assays, particularly those measuring donor-derived cell-free DNA (dd-cfDNA), are currently being investigated as early predictors of rejection [
111-
113]. Elevations in dd-cfDNA levels can precede clinical signs of graft rejection by 1–2 weeks and often outperform liver function tests in terms of sensitivity [
114]. Prospective multicenter studies are underway to validate these approaches and to establish dd-cfDNA as a routine tool for rejection surveillance [
39].
Clinicians face the challenge of predicting rejection in patients treated with ICIs for post-transplant malignancies. ICIs carry a high risk of allograft rejection; however, monitoring with dd-cfDNA may help stratify this risk. Hurkmans et al. reported a kidney transplant recipient treated with nivolumab who developed fulminant acute rejection within two weeks, preceded by a sharp increase in dd-cfDNA from 0.9% to 23% [
115]. In contrast, Lakhani et al. [
116] described another kidney recipient receiving pembrolizumab in whom serial dd-cfDNA values remained consistently <1%, allowing the continuation of therapy without rejection. Considered together, these reports suggest that serial dd-cfDNA monitoring could provide a non-invasive tool to predict and manage rejection risk during ICI therapy in transplant recipients.
There is increasing recognition of the gut microbiome as a contributor to liver transplant outcomes. Clinical investigations have shown that reduced microbial diversity is linked to post-transplant complications and distinct fecal profiles, differentiating recipients with abnormal versus stable graft function, while experimental models have demonstrated that intestinal microbial shifts could precede acute rejection events [
117-
119].
In addition to systemic ICIs, immunologically targeted local treatments have been explored. Oncolytic viruses are engineered to selectively replicate in tumor cells, inducing direct lysis and the release of tumor antigens that can promote anti-tumor immunity [
120]. Clinical efficacy has been established with T-VEC in melanoma and with G47Δ in glioblastoma in Japan [
121,
122]. An important advantage of this platform is the ability to encode immunomodulatory molecules within the viral backbone, thereby generating agents such as cytokines or ICIs directly in the tumor microenvironment. In a recent report, VG161, a modified HSV-1 encoding IL-12 and IL-15, and a PD-1/PD-L1 blocker, demonstrated encouraging safety and anti-tumor activity in a phase I trial for refractory HCC [
123]. These findings indicate that oncolytic virus-based therapies may offer a potential option in settings where systemic ICIs are limited, by enabling localized immune activation within the tumor.
Therapies designed to target tumor-specific antigens have also seen rapid development in recent years; one notable example is the application of mRNA technology. Advances in this field have enabled the development of individualized vaccines that target tumor-specific neoantigens. In a phase I trial of resected pancreatic cancer, these vaccines elicited robust and durable neoantigen-specific CD8+ T-cell responses in half of the patients, correlating with delayed recurrence [
124]. Extended follow-up demonstrated that vaccine-induced clones could persist for years in a functional, tissue-resident, memory-like state and infiltrate recurrent tumors [
125]. These findings highlight the potential of antigen-directed mRNA strategies to generate long-lived immunity tailored to each malignancy, with possible applicability to HCC. By promoting localized immune activation within the tumor microenvironment, such strategies may offer options for treating malignancies in immunosuppressed transplant recipients, thereby potentially reducing the risk of systemic rejection.
SUMMARY
LT is an established therapy for end-stage liver disease and HCC, with one-year survival rates of nearly 90% [
2]. The key challenge remains balancing immunosuppression for graft tolerance against oncogenic and metabolic risks [
7,
42-
45]. Among post-transplant complications, HCC recurrence remains a major concern, affecting 8–20% of patients and markedly affecting their survival [
48-
50]. Prognostic models (RETREAT, MORAL, and HALT-HCC) stratify recurrence risk according to tumor burden and biology, whereas biomarkers such as AFP and imaging are used for early detection, although optimal protocols remain debated [
54-
59].
Systemic therapies for uHCC have advanced with the introduction of TKIs and ICIs; however, ICI use after LT carries a high risk of acute rejection and mortality, especially when graft PD-L1 is expressed [
66,
67,
72]. Meanwhile, TKIs such as lenvatinib remain feasible and effective options in the post-transplant recurrence setting (
Fig. 4) [
91]. Looking ahead, several innovations may reshape the management of LT recipients, and among these, dd-cfDNA has emerged as a sensitive noninvasive biomarker of acute rejection, often preceding biochemical changes by 1–2 weeks [
113,
114]. Recent advances in cancer studies highlight oncolytic viruses, such as VG161 and personalized mRNA vaccines, as novel strategies capable of generating tumor-specific immune responses [
123-
125]. Together, these advances highlight a future in which integrated biomarker-driven immunosuppression and innovative immunotherapies may further improve longterm outcomes in liver transplant recipients.
FOOTNOTES
-
Authors’ Contribution
T.Y. contributed to the conception, design, and drafting of this review, and critically revised the manuscript for key intellectual content. R.T. and M.F. participated in drafting and reviewing the manuscript. All the authors have read and approved the final version of the manuscript.
-
Acknowledgements
This work was supported by the Health, Labor, and Welfare Policy Research Grants from the Ministry of Health, Labor, and Welfare of Japan (Policy Research for Hepatitis Measures [23HC2001]) and JSPS KAKENHI (Grant Numbers 24K11064 and 24K11106).
We thank BioRender.com for providing the tools used to create the figures. During the preparation of this work the author used “ChatGPT 5.2” in order to edit language and improve readability. After using this tool/service, the author reviewed and edited the content as needed and take full responsibility for the content of the publication.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.Mechanisms of T cell–mediated rejection and pharmacologic targets after liver transplantation. Rejection after LT largely depends on T cell-mediated pathways initiated by allorecognition, in which donor or recipient APCs present donor antigens. Biological agents act at this stage by depleting activated T cells. Following antigen recognition via co-stimulatory signaling, the calcineurin–NFAT–IL-2 axis is activated, promoting cytokine production and T cell proliferation; this pathway is inhibited by CNIs. Activation of the mTORC1 pathway by IL-2 and growth factor signaling leads to T cell clonal expansion and differentiation, which is blocked by mTOR inhibitors, whereas antimetabolites suppress T cell clonal expansion. Corticosteroids suppress the production of cytokines and chemokines that recruit inflammatory cells. APC, antigen-presenting cell; Ca, calcium; CNI, calcineurin inhibitor; HIF-1α, hypoxia-inducible factor 1α; IL-2, interleukin 2; LT, liver transplantation; mTOR, mechanistic target of rapamycin; mTORC1, mechanistic target of rapamycin complex 1; NFAT, nuclear factor of activated T cells.
Figure 2.Immune checkpoint inhibitors can trigger liver allograft rejection. PD-L1 on transplanted liver graft hepatocytes interacts with PD-1 on activated T cells to maintain tolerance. When this interaction is blocked by an anti-PD-1 antibody, inhibitory signaling is lost, resulting in sustained T cell activation and immune-mediated injury to hepatocytes. PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1.
Figure 3.Systemic therapy in pre- and post-transplant settings for unresectable HCC. In the pre-transplant setting, systemic therapy can enable downstaging or serve as a bridge to liver transplantation, with a recommended 50–90-day interval after ICI treatment before proceeding to transplantation. In the post-transplant setting, recurrence may be managed with TKIs, whereas the use of ICIs increases the risk of graft rejection. HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; TKI, tyrosine kinase inhibitor.
Figure 4.Importance of graft and HCC management after liver transplantation. Both graft and HCC management are essential in patients undergoing liver transplantation for HCC. Long-term care requires tailored strategies to balance immunosuppression and oncological control. HCC, hepatocellular carcinoma; ICIs, immune checkpoint inhibitors; PD-L1, programmed cell death ligand 1; TKI, tyrosine kinase inhibitor.
Table 1.Immunosuppressive agents used in liver transplantation
Table 1.
|
Drug class |
Agents |
Mechanism of action |
Clinical application |
Major adverse effects |
|
Corticosteroids |
Prednisolone, Methylprednisolone |
Suppress cytokine transcription and inflammation |
Routine induction therapy (perioperative bolus and taper) and first-line treatment for acute rejection |
Hyperglycemia, hypertension, weight gain, infection |
|
Calcineurin inhibitors (CNIs) |
Tacrolimus, Cyclosporine |
Block calcineurin/NFAT pathway; inhibit IL-2 production |
Backbone of maintenance immunosuppression; tacrolimus is generally preferred |
Nephrotoxicity, neurotoxicity |
|
Antimetabolites |
Mycophenolate mofetil (MMF), Azathioprine |
Impair purine synthesis, inhibit lymphocyte proliferation |
Adjunctive maintenance therapy to allow CNI dose reduction |
Leukopenia, gastrointestinal symptoms |
|
mTOR inhibitors |
Sirolimus, Everolimus |
Inhibit T-cell proliferation via mTOR pathway |
Adjunctive or CNI-sparing therapy, particularly in patients with renal dysfunction or selected oncologic considerations |
Hyperlipidemia, delayed wound healing, hepatic artery thrombosis |
|
Biologic agents |
Antithymocyte globulin (ATG), Basiliximab |
T-cell depletion or inhibition |
Reserved for selected cases (e.g., renal-sparing, re-transplant, or steroid-resistant rejection) |
Infections, hematologic toxicity |
Table 2.Reported cases of ICIs after LT for recurrent HCC
Table 2.
|
No |
Age |
Sex |
ICI |
Graft rejection |
Time from LT to ICI (yr) |
PD-L1 status |
Baseline immunosuppression before ICI |
Duration of ICI (wk) |
Tumor response |
OS (mo) |
Author |
Year of publication |
|
1 |
48 |
M |
Atezolizumab+Bevacizumab |
No |
2 |
NA |
Tacrolimus+MMF+steroid |
16 |
PD |
7 |
Rudolph et al. [74] |
2023 |
|
2 |
67 |
F |
Atezolizumab+Bevacizumab |
No |
1 |
NA |
Tacrolimus+MMF+steroid |
8 |
PD |
9 |
Rudolph et al. [74] |
2023 |
|
3 |
55 |
M |
Atezolizumab+Bevacizumab |
No |
1 |
Negative |
NA |
6 |
PD |
NA |
Yang et al. [73] |
2022 |
|
4 |
35 |
M |
Atezolizumab+Bevacizumab |
No |
4 |
NA |
NA |
40 |
PD |
10 |
Ben Khaled et al. [75] |
2021 |
|
5 |
54 |
M |
Nivolumab |
No |
3 |
NA |
Tacrolimus |
62 |
SD |
20 |
Zhuang et al. [76] |
2020 |
|
6 |
70 |
M |
Nivolumab |
Yes (45d) |
3< |
NA |
Tacrolimus |
8 |
PD |
4 |
Al Jarroudi et al. [77] |
2020 |
|
7 |
62 |
F |
Nivolumab |
No |
1 |
NA |
Tacrolimus |
10 |
PD |
3< |
Al Jarroudi et al. [77] |
2020 |
|
8 |
66 |
M |
Nivolumab |
No |
2 |
NA |
Tacrolimus |
12 |
PD |
3< |
Al Jarroudi et al. [77] |
2020 |
|
9 |
54 |
F |
Ipilimumab |
No |
7 |
NA |
Tacrolimus |
56 |
CR |
27 |
Pandey and Cohen [78] |
2020 |
|
10 |
62 |
F |
Nivolumab |
No |
1 |
NA |
Tacrolimus+MMF |
83 |
CR |
20 |
Amjad et al. [79] |
2019 |
|
11 |
57 |
M |
Nivolumab |
No |
3 |
NA |
Tacrolimus |
5 |
PD |
1 |
DeLeon et al. [80] |
2018 |
|
12 |
56 |
M |
Nivolumab |
No |
8 |
Negative |
Sirolimus+MMF |
5 |
PD |
1 |
DeLeon et al. [80] |
2018 |
|
13 |
35 |
F |
Nivolumab |
No |
4 |
Negative |
Tacrolimus |
5 |
PD |
1 |
DeLeon et al. [80] |
2018 |
|
14 |
64 |
M |
Nivolumab |
No |
1 |
NA |
Tacrolimus |
1 |
NA |
0 |
DeLeon et al. [80] |
2018 |
|
15 |
68 |
M |
Nivolumab |
Yes (27d) |
1 |
Positive |
Sirolimus |
4 |
NA |
1 |
DeLeon et al. [80] |
2018 |
|
16 |
57 |
M |
Pembrolizumab |
No |
3 |
NA |
Tacrolimus+everolimus+steroid |
40 |
CR |
10< |
Rammohan et al. [81] |
2018 |
|
17 |
53 |
F |
Nivolumab |
Yes (lethal: 7d) |
3 |
NA |
Everolimus+MMF |
2 |
NA |
1 |
Gassmann et al. [82] |
2018 |
|
18 |
41 |
M |
Nivolumab |
No |
1 |
NA |
Tacrolimus |
30 |
PD |
7< |
De Toni and Gerbes [83] |
2017 |
|
19 |
20 |
M |
Nivolumab |
Yes (lethal: 17d) |
3 |
Positive |
Sirolimus |
4 |
NA |
1 |
Friend et al. [84] |
2017 |
|
20 |
14 |
M |
Nivolumab |
Yes (lethal: 7d) |
1 |
Positive |
Tacrolimus |
2 |
NA |
1 |
Friend et al. [84] |
2017 |
|
21 |
70 |
M |
Pembrolizumab |
No |
8 |
NA |
TAcrolimus |
11 |
PD |
3 |
Varkaris et al. [85] |
2017 |
Abbreviations
antibody-mediated rejection
donor-derived cell-free DNA
European Association for the Study of the Liver
hypoxia-inducible factor 1α
immune checkpoint inhibitors
mechanistic target of rapamycin
mechanistic target of rapamycin complex 1
nuclear factor of activated T cells
programmed cell death protein 1
programmed death-ligand 1
transarterial chemoembolization
tyrosine kinase inhibitors
University of California San Francisco
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