INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignancies worldwide, and ranks as the third leading cause of cancer-related deaths¹. Advanced HCC -defined as an unresectable or metastatic disease- has a poor prognosis, with a median survival of approximately 6 months in the absence of treatment and a 5-year survival rate below 10%. In 2008, the introduction of the oral tyrosine kinase inhibitor (TKI), sorafenib, marked a milestone, demonstrating an overall survival (OS) benefit in patients with HCC for the first time². Following the approval of sorafenib, lenvatinib was established as a non-inferior first-line alternative in the phase III REFLECT trial, achieving a median OS of 13.6 months compared with 12.3 months for sorafenib, together with superior progression-free survival (PFS) and objective response rates³. Subsequently, the clinical development and application of immune checkpoint inhibitors (ICIs) targeting programmed cell death-protein 1 (PD-1), programmed cell death-protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have redefined the treatment paradigm for advanced HCC, representing a significant advancement in treatment options. Combination immunotherapy incorporating these agents have significantly improved clinical outcomes and OS in pivotal phase III trials. The key phase III trials include IMbrave150 (atezolizumab plus bevacizumab), HIMALAYA (tremelimumab plus durvalumab), and CheckMate-9DW (nivolumab plus ipilimumab)^4-6. All three combinations demonstrated substantial survival benefits in phase III clinical studies compared to that with TKIs, such as sorafenib or lenvatinib. Despite these therapeutic breakthroughs, the use of ICIs may lead to immune-related adverse events (irAEs) owing to dysregulated immune activation. These events can involve virtually every organ system, ranging from mild manifestations (e.g., rash and thyroiditis) to severe or life-threatening complications such as colitis, pneumonitis, myocarditis, or hepatic failure^7,8. In HCC, the incidence of hepatic irAEs is elevated due to the frequent presence of pre-existing hepatic dysfunction, often resulting from chronic hepatitis or cirrhosis. These underlying conditions not only enhance the susceptibility to hepatic irAEs but also complicate their management, requiring tailored therapeutic approaches^9-11. Consequently, a thorough understanding of the incidence, mechanisms, and management approaches for ICI-related irAEs is crucial for optimizing clinical outcomes in this patient population. This review presents an in-depth summary of the clinical manifestations, underlying mechanisms, and organ-specific management strategies for irAEs in advanced HCC, incorporating insights from recent clinical trials and updated international guidelines, to offer practical guidance for evidence-based clinical practice.

INCIDENCE OF IMMUNE-RELATED ADVERSE EVENTS IN ADVANCED HEPATOCELLULAR CARCINOMA

With the expanding clinical application of ICIs as a first-line therapy for advanced HCC, understanding their safety profile, particularly the incidence and spectrum of irAEs, is of increasing clinical importance. The incidence data from pivotal phase III trials that established immunotherapy-based regimens for HCC are summarized in Fig. 1^4,6,12,13.

The first phase III trial to demonstrate the superiority of combination immunotherapy over sorafenib in unresectable HCC was the IMbrave150 trial, which compared atezolizumab plus bevacizumab with sorafenib. This combination significantly improved OS (median OS, 19.2 vs. 13.4 months) and PFS (median PFS, 6.9 vs. 4.3 months). However, treatment-related adverse events of grade ≥3 occurred in 43% of patients, and grade ≥3 irAEs attributed to atezolizumab were observed in 29%, with hepatitis being the most frequent (25%), and 12% of patients requiring corticosteroids⁴. Severe dermatologic or gastrointestinal irAEs such as rash or colitis were uncommon, occurring in approximately 1% of the patients.

In the HIMALAYA trial, the STRIDE regimen (tremelimumab plus durvalumab) improved OS compared to that with sorafenib (median OS, 16.4 vs. 13.8 months)¹⁴. Despite dual ICI therapy, the overall incidence of grade ≥3 irAEs was relatively low at 12.6%, which may be attributed to the limited CTLA-4 exposure inherent to the STRIDE regimen. In this regimen, tremelimumab was administered as a single priming dose rather than as continuous combination therapy. Severe events were infrequent, with most irAEs, such as hepatitis, diarrhea, or colitis, occurring in only 1-2% of patients (Table 1). Approximately 20% of the patients required corticosteroids for irAE management.

In contrast, another dual ICI regimen combining nivolumab and ipilimumab, evaluated in the CheckMate-9DW trial, achieved the longest median OS (23.7 months) among the published phase III studies⁶. However, this regimen was associated with substantial irAEs, and treatment-related deaths were reported in approximately 4% of the patients, highlighting the need for vigilant monitoring and early management of severe adverse events. Grade ≥3 irAEs occurred in 28% of patients, with hepatitis being the most common severe event (15%), followed by diarrhea/colitis (5%) and rash (4%)⁶. High-dose corticosteroids were required in approximately 29% of the patients. Endocrine irAEs, including adrenal insufficiency and hypophysitis, were also reported (1- 2%) (Table 1).

Overall, the incidence and severity of irAEs vary across regimens and appear to correlate with the number, type, and dosage of immune checkpoint targets. Dual ICI combination therapy, typically administered during the induction phase, significantly improves survival outcomes, but is accompanied by a higher incidence of irAEs, particularly within the first 3 months of treatment. Therefore, vigilant monitoring, early detection, prompt initiation of corticosteroid therapy, and multidisciplinary management are essential, particularly during early treatment.

PATHOPHYSIOLOGY OF IMMUNE-RELATED ADVERSE EVENTS

ICIs target inhibitory immune checkpoints, including the PD-1/PD-L1 and CTLA-4 pathways, thereby releasing T-cell activation from negative regulatory control and enhancing antitumor immune responses^15,16. Although this mechanism underlies therapeutic efficacy, it can also disrupt peripheral immune tolerance and precipitate immune-mediated inflammation in normal tissues. The pathogenesis of irAEs involves five interrelated immunopathogenic processes (Fig. 2).

Enhanced T-cell autoimmunity

Checkpoint blockade activates effector CD8⁺ and CD4⁺ T-cells that recognize self-antigens shared between tumor and normal tissues. This cross-reactivity leads to autoimmune inflammation and tissue injury¹⁷. The destruction of tumor cells further releases self-antigens, promoting epitope spreading and amplifying autoreactive T-cell responses^17-19.

Autoantibody formation

CTLA-4 inhibition promotes the activation of autoreactive B cells, leading to the generation of de novo or increased autoantibodies^20,21. Elevated serum autoantibody levels correlate with the onset and severity of irAEs, supporting an antibody-mediated component of immune toxicity²².

Pro-inflammatory cytokine expansion

CTLA-4 blockade drives expansion of interleukin (IL)-17-secreting T helper 17 (Th17) cells, while PD-1 inhibition enhances Th1-skewed responses with overproduction of interferon gamma, tumor necrosis factor-alpha (TNF-α), and IL-2^23-26. In addition, increased circulating IL-6, IL-1β, and CXCL9-11 establish a pro-inflammatory milieu that recruits macrophages and natural killer cells, sustaining tissue inflammation and damage.

Anti-CTLA-4 complement activation

Anti-CTLA-4 antibodies can bind to CTLA-4 expressed on normal cells, most notably pituitary cells, and trigger complement-dependent cytotoxicity, leading to localized inflammation and endocrine irAEs such as hypophysitis²⁷.

Innate immune activation

Innate immune cells play a pivotal role in the progression of tissue injury. Histopathological analyses of ICI-induced hepatitis have revealed dense infiltration of CD8⁺ T cells and CD68+ macrophages^28,29. Preclinical models have confirmed that macrophage-T-cell crosstalk and myeloid-cell activation drive hepatocellular damage through cytokine amplification loops^30,31. Excessive innate immune activation manifests clinically in autoinflammatory patterns, including ICI-induced colitis and hepatitis.

In HCC, the immunopathogenesis of irAEs occurs in a distinctive background of cirrhosis-associated immune dysfunction (CAID), which represents a paradoxical state of systemic inflammation coexisting with immune exhaustion^32-34. Chronic liver injury and fibrosis alter both innate and adaptive immunity, characterized by the persistent activation of Kupffer cells, increased circulating endotoxins, and reduced pathogen clearance. These abnormalities compromise the hepatic immune tolerance and sensitize the liver to excessive inflammation once ICI therapy is initiated. Furthermore, disruption of the gut-liver axis and translocation of microbial products through the permeable intestinal barrier promote continuous antigenic stimulation of hepatic macrophages, perpetuating inflammatory signaling within the portal microenvironment³⁵. Consequently, ICI therapy in patients with HCC can provoke exaggerated hepatic inflammation and hepatocellular necrosis. Furthermore, hepatic irAE reported occur more frequently in HCC than in other solid tumors³⁶. However, despite their increased frequency, hepatic irAEs have not been reported to have a detrimental impact on the overall survival of these patients.

Together, these findings highlight that CAID and gut-liver axis alterations act as amplifying cofactors for hepatic irAEs, superimposing the general mechanisms of immune dysregulation described in Fig. 2. In HCC, these mechanisms are compounded by CAID and disruption of the gut-liver axis, resulting in increased vulnerability to hepatotoxicity. A comprehensive understanding of these immune pathways is essential to guide early detection and patient-tailored management of irAEs in clinical practice.

IMMUNE-RELATED ADVERSE EVENT MANAGEMENT

General management

The early recognition and appropriate management of irAEs are critical for optimizing both safety and treatment continuity during ICI therapy. In patients with HCC, the presence of underlying liver disease and comorbidities further complicates clinical assessment, emphasizing the importance of systematic monitoring and prompt intervention.

According to the HIMALAYA study, most irAEs occur within the first 3 months of treatment¹³. Similarly, the Check-Mate-9DW trial reported that treatment-related adverse events, including hepatic and dermatologic irAEs, typically emerge early -most often within the first month of therapy and less frequently beyond 3 months- with their incidence decreasing over time. These findings highlight the importance of vigilant monitoring during the initial treatment period to prevent mild symptoms from progressing into severe events.

Patients should be educated to recognize potential irAE symptoms, and structured follow-up assessments should be conducted at each visit -and, when necessary, between visits,- to detect early signs of organ inflammation^37-39. When irAEs are suspected, differential diagnosis is essential to exclude alternative causes such as infection, tumor progression, or drug-induced toxicity. Once an irAE is confirmed or strongly suspected, management should be guided by the severity of toxicity, as graded by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).

In general, patients with grade 1 irAEs can continue ICI therapy with close monitoring, whereas those with grade ≥2 toxicities require temporary treatment interruption and initiation of corticosteroids. For grade 3 or higher events, ICI discontinuation is typically recommended along with high-dose corticosteroid therapy (prednisone 1-2 mg/kg/day or equivalent). Intravenous administration is preferred for severe organ involvement such as pneumonitis, colitis, or hepatitis. Corticosteroids should be tapered gradually over at least 4 to 6 weeks to minimize relapse risk. If symptoms fail to improve within 48-72 hours despite corticosteroid therapy, escalation to second-line immunosuppressive agents, such as infliximab for colitis or mycophenolate mofetil (MMF) for hepatitis, should be considered according to organ-specific guidelines. The European Society for Medical Oncology (ESMO) clinical practice guidelines^38, American Society of Clinical Oncology (ASCO)^37, National Comprehensive Cancer Network (NCCN)^40, and Society for Immunotherapy of Cancer (SITC)³⁹ emphasize a multidisciplinary approach involving oncologists and relevant organ specialists for comprehensive management and follow-up evaluation.

A summarized framework for the general management of irAEs according to severity (CTCAE v5.0), adapted from the ESMO and ASCO, is presented in Table 2. These guidelines provide a practical stepwise algorithm for toxicity grading, timing of corticosteroid initiation, and criteria for treatment resumption.

In patients with advanced HCC, the manifestations of irAEs are often complex because of pre-existing liver disease, such as chronic viral hepatitis or cirrhosis, and other comorbid conditions. Therefore, management requires a meticulous and individualized approach that differs from the strategies used for other malignancies. Clinicians should be familiar with organ-specific management principles for the major toxicities most frequently observed in the skin, liver, gastrointestinal tract, lungs, and endocrine system. The following section provides an overview of organ-specific management strategies that are clinically relevant for optimizing the care of patients with advanced HCC receiving immunotherapy.

Organ-specific management

IrAEs are generally categorized based on the organ system involved. Although systemic corticosteroids remain the cornerstone of treatment for moderate to severe irAEs (grade ≥2), the optimal management approach should be tailored to the specific organ involved and the clinical context.

Accordingly, organ-specific management of irAEs should adhere to the structured, severity-based algorithm outlined in the ESMO clinical practice guidelines^38, which serves as the primary framework for this review. To ensure cross-guideline consistency, complementary recommendations from the SITC^33, ASCO^37, and NCCN³⁴ guidelines were reviewed and integrated (Table 3). These consensus frameworks collectively emphasize standardized grading, timely corticosteroid initiation, and coordinated multidisciplinary management to ensure optimal clinical outcomes.

Table 3 provides a consolidated summary of the management strategies for major organ systems based on CTCAE v5.0. The table outlines stepwise interventions, including corticosteroid initiation, tapering schedules, and escalation to second-line immunosuppressive therapy, reflecting the current international standards for toxicity assessment and management across diverse clinical contexts.

Hepatic irAE (hepatitis)

Hepatic irAEs are among the most clinically significant in HCC, reflecting the high prevalence of underlying chronic liver disease and limited hepatic functional reserve in this population. The incidence of hepatic irAEs varies across pivotal trials (53% in IMbrave150, 3% in HIMALAYA, and 19% in CheckMate-9DW) with grade ≥3 events reported in 25%, 1%, and 15% of patients, respectively. Treatment-related deaths occurred in up to 4% of patients in the CheckMate-9DW study, primarily due to hepatic failure, underscoring the need for early recognition and timely intervention⁶.

The incidence of hepatic irAEs in HCC is elevated, primarily because of the frequent presence of pre-existing hepatic dysfunction, often resulting from chronic hepatitis or cirrhosis. Additionally, these events tend to manifest significantly earlier in patients with HCC than in those with other solid tumors³⁶. Many patients remain asymptomatic, with hepatic enzyme elevation being the only indication of hepatic irAE, whereas others develop fatigue, fever, right upper quadrant discomfort, or jaundice⁴¹.

The differential diagnosis of hepatic enzyme elevation in patients with HCC includes exacerbation of chronic liver disease (e.g., hepatitis B virus/hepatitis C virus reactivation and alcoholic or metabolic dysfunction-associated steatohepatitis), tumor progression (portal vein invasion or parenchymal loss), biliary obstruction, ischemic hepatitis, drug-induced liver injury, autoimmune hepatitis, and hepatic vascular disorders such as Budd-Chiari. Grading should incorporate aspartate aminotransferase/alanine aminotransferase [AST/ALT] and bilirubin levels in conjunction with the overall hepatic function through, close laboratory and clinical monitoring⁴¹.

The management of hepatic irAEs should follow a severity-based algorithm, as summarized in Table 3. For grade 1 hepatotoxicity, ICIs can be continued with close laboratory monitoring (every 1-2 week), and hepatotoxic medications should be avoided. For grade 2 events, ICIs should be withheld, and corticosteroid therapy (prednisolone 0.5-1.0 mg/kg/day) should be initiated if enzyme levels fail to improve or continue to rise. Once the liver function normalizes, corticosteroids should be tapered to <10 mg/day before resuming ICI therapy.

For grade ≥3 hepatitis, ICIs must be discontinued, and high-dose intravenous methylprednisolone (1-2 mg/kg/day) should be initiated promptly. The ESMO clinical practice guidelines provide a more detailed stratification of grade 3 hepatitis based on AST/ALT and bilirubin levels, which can guide corticosteroid dosing and inpatient management. If no improvement is observed within 48-72 hours of appropriate corticosteroid therapy, MMF should be introduced, and infliximab should be avoided due to its hepatotoxic potential. During refractory events, escalation to tacrolimus, azathioprine, cyclosporine, or tocilizumab should be considered under multidisciplinary supervision. In fulminant or rapidly progressive cases, pulse-dose methylprednisolone (500-1,000 mg/day for 3-5 days) may be used in specialized centers, although major guidelines recommend restricting this approach to life-threatening hepatic failure.

Dermatologic irAE (rash)

Cutaneous irAEs, particularly rashes, are among the most commonly observed irAEs associated with ICIs. In clinical trials, the incidence of dermatologic irAEs varies: 22% in IMbrave150 (1% for grade ≥3), in 2% HIMALAYA (<1% for grade ≥3), and 15% in CheckMate-9DW (4% for grade ≥3). These events typically manifest early, within the first 4-6 weeks of therapy, and are commonly observed as maculopapular rashes that are, often associated with pruritus. In mild cases, symptoms generally resolve with symptomatic management, including the use of topical corticosteroids and oral antihistamines⁴².

For grade 2 and grade 3, if refractory to corticosteroids, ICI therapy should be withheld, and systemic corticosteroids (prednisone 0.5-1.0 mg/kg/day) should be initiated. If no improvement is observed, escalation to methotrexate or MMF should be considered. In the event of grade 4 dermatologic irAEs, ICI therapy should be permanently discontinued, and high-dose intravenous corticosteroids (1-2 mg/kg/day methylprednisolone) should be initiated immediately. Steroid-refractory reactions should be managed with additional immunosuppressive therapies, such as infliximab or tocilizumab. Early dermatological involvement of dermatology is critical for determining the need for systemic therapy.

Severe skin reactions, such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but can be life-threatening and require immediate intervention. If SJS and TEN are suspected, ICI therapy is permanently discontinued immediately; intravenous immunoglobulin (IVIG) may be considered in combination with steroid therapy, and multidisciplinary intensive care is required^40,43. These findings highlight the importance of early recognition and aggressive management to minimize severe complications while continuing ICI therapy.

Gastrointestinal irAE (diarrhea/colitis)

Gastrointestinal irAEs, including diarrhea and colitis, are among the most frequently observed irAEs in patients treated with ICIs. The incidence of these events varies across clinical trials: in the IMbrave150, HIMALAYA, and CheckMate-9DW studies, diarrhea and colitis occurred in 3%, 2%, and 8% of patients, respectively, with grade ≥3 events reported in 1%, 2%, and 5% of patients. The severity of these events ranges from mild diarrhea to more serious manifestations, including severe abdominal pain, fever, bloody stools, and systemic inflammatory responses.

In patients with grade 1 diarrhea or colitis, symptomatic management, including the administration of antidiarrheal agents (e.g., loperamide) and a low-fiber diet, is typically sufficient, and ICI therapy may be continued with careful monitoring. In cases of grade 2 or more severe events, ICI therapy should be withheld, and systemic corticosteroids (prednisone 40-60 mg/day) should be initiated. If steroid therapy proves ineffective, second-line agents such as infliximab, a TNF-α inhibitor, or vedolizumab, an intestinal-specific anti-integrin monoclonal antibody, may be considered. Additional immunosuppressants, such as ustekinumab (IL-12/IL-23 inhibitor), tofacitinib (Janus kinase 1/3 inhibitor), or fecal microbiota transplantation, may be employed depending on the clinical course and severity.

Caution is warranted when considering the administration of tocilizumab (an anti-IL-6 receptor antibody) in instances of colitis-related irAEs, owing to the potential risk of intestinal perforation^44,45. Early involvement of a multidisciplinary team, including gastroenterologists, is essential to ensure the optimal management of these complex and potentially debilitating toxicities.

Endocrine irAE (hypothyroidism/hyperthyroidism)

Endocrine irAEs, particularly hypothyroidism and hyperthyroidism, are commonly observed in patients treated with ICIs. The incidence of thyroid dysfunction varies across clinical trials, with hypothyroidism reported in 14% of patients in IMbrave150, 10% in HIMALAYA, and 19% in CheckMate-9DW, with grade ≥3 events observed in less than 1% of patients in each study. Hyperthyroidism has been reported in approximately 5% of patients in IMbrave150, 5% in HIMALAYA, and 11% in CheckMate- 9DW, with grade ≥3 events being uncommon (<1% in each study). These irAEs are generally observed early during treatment and, most commonly occur within the first 4-6 weeks of therapy.

Thyroid dysfunction generally presents as hypothyroidism, characterized by elevated thyroid-stimulating hormone (TSH), or hyperthyroidism, with elevated free thyroxine (FT4) levels. In grade 1 thyroid dysfunction, which is usually asymptomatic or minimally symptomatic with mild abnormalities in TSH or FT4 levels, ICI therapy can typically be continued with close monitoring. For grade 2 thyroid dysfunction, which may present with symptoms such as fatigue, weight gain, or mild hyperthyroidism, thyroid hormone replacement therapy for hypothyroidism or beta-blockers for hyperthyroidism should be initiated. In grade 3 thyroid dysfunction, characterized by severe symptoms such as myxedema or thyroid storm, urgent intervention is required. For hypothyroidism, levothyroxine therapy should be initiated, with dose adjustments based on TSH and FT4 levels. In hyperthyroidism, beta-blockers (e.g., propranolol) are used for symptom management, and antithyroid agents, such as carbimazole, are indicated for Graves' disease⁴⁶. If thyroiditis is present, corticosteroids (prednisone 0.5 mg/kg/day) may be prescribed, tapering the dose as the symptoms improve. For grade ≥3 thyroid dysfunction that is symptomatic or persistent, ICI therapy should be withheld, and appropriate endocrine treatment should be implemented.

Corticosteroids (prednisolone 0.5 mg/kg) for painful thyroiditis may be considered, with close monitoring of thyroid function to ensure proper dosing and avoid complications. As thyroid dysfunction following ICI therapy is associated with favorable survival outcomes^47, timely detection and effective management of this irAE are critical for optimizing patient outcomes.

Endocrine irAE (hypophysitis)

Hypophysitis, a rare but significant irAE, occurs in a small subset of patients receiving ICIs, primarily anti-CTLA-4 therapy, and is attributed to the expression of CTLA-4 protein in human pituitary cells, particularly in adrenocorticotropic hormone (ACTH)- secreting cells. The incidence of hypophysitis is 3% of patients CheckMate-9DW, with grade ≥3 events reported in 1% of patients. When ipilimumab binds to these CTLA-4 molecules, pituitary cells themselves become targets of autoantibodies through an antigen-mimicking mechanism, leading to complement activation, cellular injury, and subsequent inflammatory responses that culminate in hypophysitis.

Clinical manifestations are variable and may include headache, fatigue, hyponatremia, and visual disturbances. The principal pathophysiology involves anterior pituitary hormone deficiency, resulting in impaired secretion of ACTH, TSH, luteinizing hormone/follicle-stimulating hormone, prolactin, insulin-like growth factor-1, and gonadal hormones. Pituitary enlargement can be detected using imaging in a subset of patients.

Clinical severity ranges from subclinical presentation to life-threatening adrenal insufficiency. Management should begin with prompt glucocorticoid replacement to avoid adrenal crisis, followed by stepwise repletion of additional deficient pituitary hormones as indicated. Corticosteroid dosing was tailored to inflammatory severity (high-dose for acute/severe presentations with gradual tapering once stable). ICIs may be resumed after clinical stabilization and adequate hormonal control; however, therapy should be withheld for uncontrolled or severe hypophysitis.

Pulmonary irAE (pneumonitis)

Pneumonitis is an uncommon, but clinically significant irAE that occurs during ICI therapy. The incidence of pneumonitis varies across pivotal trials (2% in IMbrave150, 1% in HIMALAYA, and 2% in CheckMate-9DW) with grade ≥3 events reported in <1% of patients. Although rare, pneumonitis can be life-threatening and presents with a wide clinical spectrum ranging from asymptomatic radiological infiltrates to cough, dyspnea, and hypoxemia.

A differential diagnosis is essential to distinguish immune-related pneumonitis from infection, tumor progression, drug-induced interstitial lung disease, or radiation pneumonitis. Diagnostic evaluation should include high-resolution computed tomography imaging, microbiological work-up, and, when feasible and clinically tolerable, bronchoalveolar lavage with or without transbronchial biopsy.

Management is guided by CTCAE v5.0 grading and early initiation of corticosteroid therapy, which critically influences outcomes. Mild (grade 1) pneumonitis may be observed with close monitoring, and low-dose corticosteroids may be considered if the symptoms progress. For moderate to severe (grade ≥2) pneumonitis, ICIs should be withheld, and systemic corticosteroids (prednisone or methylprednisolone 1-2 mg/kg/day) initiated with a gradual taper over at least 4-6 weeks once improvement is achieved.

If symptoms fail to improve within 48-72 hours, second-line immunosuppressants such as MMF or intravenous IVIG should be considered. Infliximab is generally discouraged for pneumonitis because of its limited efficacy and increased risk of infection. In the most severe presentations, particularly when pneumonitis progresses to acute respiratory distress syndrome (ARDS), intravenous pulse-dose methylprednisolone therapy (1,000 mg/day for 3-5 days) may be considered.

Cardiac irAE (myocarditis)

Although rare, ICI-associated myocarditis is associated with an extremely high mortality rate, making early detection and prompt, aggressive treatment essential. The clinical presentation of myocarditis can range from asymptomatic elevations in cardiac enzyme levels to more severe manifestations, including arrhythmias, conduction abnormalities, heart failure, and cardiogenic shock. Consequently, any patient suspected of having myocarditis should immediately discontinue ICIs and undergo a comprehensive cardiac evaluation.

In grade 3-4 myocarditis, ICIs must be permanently discontinued, and high-dose intravenous corticosteroids should be administered as the standard treatment. If necessary, pulse-dose methylprednisolone therapy (500-1,000 mg/day for 3-5 days) should be initiated⁴⁰. In steroid-refractory myocarditis, MMF and/or IVIG are commonly employed; abatacept is increasingly favored based on emerging prospective data and ongoing randomized trials. Infliximab is generally discouraged in myocarditis (heart failure risk), and other salvage options (e.g., anti-thymocyte globulin) may only be considered in highly selected refractory cases within a multidisciplinary framework. Mechanical circulatory support should be provided, indicated.

PULSE-DOSE METHYLPREDNISOLONE THERAPY IN SEVERE IMMUNE-RELATED ADVERSE EVENTS

Oral prednisone at 1-2 mg/kg was effective in managing most moderate-to-severe irAEs. However, some patients require short-term ultra-high-dose intravenous corticosteroids (pulse-dose methylprednisolone therapy). Pulse-dose methylprednisolone therapy typically involves the administration of intravenous (IV) methylprednisolone at 500-1,000 mg/day for 3-5 days, followed by a transition to standard high-dose corticosteroid therapy (1-2 mg/kg), with gradual tapering over 4-6 weeks. Indications for pulse-dose methylprednisolone therapy include neurotoxicity-related encephalitis, Guillain-Barré syndrome, myasthenia gravis, hematologic toxicity-related hemophagocytic lymphohistiocytosis (HLH), pulmonary toxicity-related ARDS, cardiovascular toxicity-related myocarditis, and musculoskeletal toxicity-related giant cell arteritis (GCA) with ocular complications. It may also cause hepatic toxicity, specifically acute liver failure, such as fulminant hepatitis, which requires careful clinical judgment⁴⁸. Table 4 shows the management approaches for severe irAEs requiring pulse-dose methylprednisolone therapy.

Pulse-dose methylprednisolone therapy is associated with risks, including hyperglycemia, infection, and psychosis, necessitating strict patient selection. Administration must be conducted in a monitored hospital setting or intensive care unit. After 3-5 days of 500-1,000 mg/day pulse-dose methylprednisolone therapy, patients should be transitioned to oral prednisone at 1-2 mg/kg, with tapering over 4-6 weeks. If no response is observed following pulse-dose methylprednisolone therapy, additional immunosuppressants should be promptly introduced, and a multidisciplinary consultation is essential.

SECOND-LINE MANAGEMENT STRATEGIES FOR STEROID-REFRACTORY IMMUNE-RELATED ADVERSE EVENTS

Patients with irAEs unresponsive to corticosteroids were defined as those showing no clinical improvement within 48-72 hours after the initiation of high-dose corticosteroids, typically methylprednisolone at 1-2 mg/kg/day or 500-1,000 mg/day administered as pulse-dose methylprednisolone therapy for 3-5 days in life-threatening situations. Therefore, it is essential to introduce secondary immunosuppressive agents, tailored to organ-specific toxicity profiles.

For hepatic irAEs, MMF is the first-line treatment, and infliximab is avoided because of the risk of hepatic failure. Recent reports suggest that, in steroid- and MMF-refractory cases, agents such as tacrolimus, azathioprine, cyclophosphamide, and rituximab have been used, with clinical improvement observed in some patients^49-51.

Infliximab (5 mg/kg IV) or vedolizumab (300 mg IV) is recommended for treating gastrointestinal irAEs (e.g., colitis). In refractory events, alternative treatments include high-dose infliximab retreatment, fecal microbiota transplantation, ustekinumab, or tofacitinib^52,53.

In the case of pulmonary irAEs (severe pneumonia/ARDS), if unresponsive to high-dose corticosteroids, escalation with MMF or IVIG (±cyclophosphamide) is favored; anti-TNF is not preferred and should be avoided if infection is suspected; tocilizumab remains an investigational/selected option.

If myocarditis is, refractory to corticosteroids, MMF, IVIG, or anti‐T‐lymphocyte globulin may be used. Abatacept is increasingly incorporated as salvage therapy; infliximab is contraindicated; tocilizumab is not a standard second-line agent^54,55.

For neurological irAEs (e.g., encephalitis, Guillain-Barré syndrome, myasthenia gravis), IVIG or plasmapheresis are recommended as standard second-line treatments. In some instances, rituximab, tacrolimus, or cyclophosphamide may be considered^56,57.

For hematological (e.g., HLH), therapies such as IVIG, etoposide, anakinra, ruxolitinib, and tocilizumab are used in addition to steroids⁵⁸.

Among the musculoskeletal irAEs, GCA requires prompt treatment, particularly in high-risk patients with visual symptoms. These patients received intravenous methylprednisolone (500-1,000 mg/day for 3 days), followed by tapering of oral prednisone. Steroid-sparing agents such as IL-6 inhibitors (tocilizumab and sarilumab) should be considered^59,60.

Fig. 3 presents a schematic representation of the treatment algorithm for irAEs associated with ICIs. This diagram systematically outlines the stepwise treatment strategy, beginning with corticosteroid therapy as the first-line treatment, followed by the use of organ-specific second-line immunosuppressants in cases unresponsive to steroids.

CONCLUSION

The increasing use of ICIs for HCC underscores the importance of effectively managing irAEs. IrAEs are autoimmune disorders that can affect almost every organ system; thus, recognition and prompt intervention are critical for improving prognosis. In patients with HCC, the presence of chronic liver disease often complicates the clinical presentation of irAEs, as symptoms may overlap with underlying liver conditions, making thorough monitoring and initial evaluation essential.

The manifestations and severity of irAEs vary by organ and are influenced by the mechanism and dosing of ICIs, necessitating organ-specific, tailored diagnostic and therapeutic approaches. Hepatologic, dermatologic, gastrointestinal, endocrine, and pulmonary irAEs are commonly reported. Skin toxicity, colitis, and thyroid dysfunction are relatively more frequent in patients treated with PD-(L)1 inhibitors, whereas CTLA-4 inhibitors are associated with a higher incidence of systemic toxicities, such as colitis. Given the differences in adverse effect profiles among organ systems, comprehensive diagnostic evaluations, including laboratory tests, imaging studies, and histological confirmation are essential for appropriate treatment.

The overall incidence of irAEs in HCC is comparable to that observed in other solid tumors. However, hepatic irAEs occur more frequently because of the high prevalence of pre-existing hepatic dysfunction. These events may involve both hepatocellular and cholangiocytic injuries, and when superimposed on cirrhosis and systemic inflammation, they markedly increase the risk of hepatic failure. Differentiating hepatic irAEs from tumor progression or drug-induced liver injury is often challenging, underscoring the importance of a comprehensive assessment with serial liver function tests, cross-sectional imaging, and histopathological confirmation, when necessary. Because hepatic irAEs directly affect treatment continuity and clinical outcomes, vigilant monitoring and individualized immunosuppressive management are crucial, particularly for patients with advanced hepatic impairment.

For severe (grade ≥3) irAEs, high-dose steroid therapy is the cornerstone of treatment. Guidelines recommend the administration of 1-2 mg/kg/day with pulse-dose methylprednisolone therapy in life-threatening situations. Short-term high-dose steroid use has not been associated with reduced efficacy of cancer treatment, and early high-dose steroid therapy contributes to the early suppression of irAEs and improved prognosis. In suspected severe cases, steroid therapy should be initiated as soon as possible after the onset of symptoms. For steroid-refractory irAEs, particularly those involving vital organs, prompt addition of secondary immunosuppressive agents tailored to specific organ toxicity profile is essential. Furthermore, broad-spectrum antibiotics, antivirals, and vaccinations should be concurrently administered as preventive measures to minimize the risk of infection during immunosuppressive therapy.

Therefore, a major challenge for future investigations is the development of strategies to predict and effectively respond to irAEs early in treatment. Reliable predictive biomarkers for hepatic irAEs remain scarce, and although some cytokine changes and genetic factors have been linked to risk, their clinical applicability is limited. The development of predictive models that integrate individual immunological and genetic characteristics is necessary, along with the clinical validation of new immunomodulatory strategies, such as IL-6 inhibitors. Furthermore, while irAE management in patients with HCC currently follows the general guidelines for solid tumors, the higher frequency of hepatitis and liver failure due to cirrhosis and underlying liver disease highlights the need for HCC-specific irAE management guidelines, tailored to the characteristics of this patient population and differentiated by treatment regimens.

Article information

Conflicts of Interests

Hong Jae Chon has received speaker honoraria from Eisai, Roche, ONO, MSD, Bristol Myers Squibb, BeiGene, Sanofi, Servier, AstraZeneca, and Boryung; he is a consultant/advisory board member for Eisai, Roche, ONO, MSD, Bristol Myers Squibb, BeiGene, Servier, AstraZeneca, Boryung, IMBDx, and Aptamer Science; he received grants from Roche, BeiGene, IMBDx, Dong-A ST, and Boryung. Hong Jae Chon is an editorial board member of Journal of Liver Cancer, and was not involved in the review process of this article. All other authors declare no conflict of interest.

Ethics Statement

This review article is fully based on articles which have already been published and did not involve additional patient participants. Therefore, IRB approval is not necessary.

Funding Statement

This research was funded by the Korean Liver Cancer Association Research Award (2023) and the National Research Foundation of Korea (NRF) grants, supported by the Korean government (MSIT): grant numbers NRF-2023R1A2C2004339 to Hong Jae Chon.

Data Availability

Not applicable.

Author Contributions

Conceptualization: SKC, SW, HJC

Data curation: SKC, SW

Methodology: SKC, SW, HJC

Supervision: HJC

Visualization: SKC, SW

Writing - original draft preparation: SKC, SW, HJC

Writing - review & editing: SKC, SW, HJC

Figure 1.

Incidence of immune-checkpoint inhibitor-induced adverse events classified by organ system. Data were collected from four positive phase III clinical trials of first-line treatment in advanced hepatocellular carcinoma (IMbrave150, HIMALAYA, CARES-310, CheckMate-9DW). Incidences reported in ≥2 trials are presented as ranges. Events reported in a single trial are not shown. For hepatitis, incidences showed considerable variation across trials. Therefore, data from each study were presented separately. Colors indicate maximum incidence of all grade immune-related adverse events (%). irAE, immune-related adverse events; G, grade.

Figure 2.

Pathophysiology of immune-related adverse events. 1) Enhanced T-cell autoimmunity: checkpoint inhibition releases effector CD8+ and CD4+ T cells from negative regulatory control, leading to cross-reactive T-cell responses against self-antigens shared with tumor cells and resulting in autoimmune-like tissue injury. 2) Autoantibody formation: CTLA-4 blockade enhances autoreactive B-cell activation, promoting production of self-reactive antibodies that mediate tissue injury through Fc- and complement-dependent mechanisms. 3) Proinflammatory cytokine expansion: Th1 and Th17 polarization drives overproduction of IFN-γ, TNF-α, IL-2, IL-6 and IL-17, establishing a proinflammatory cytokine milieu that recruits macrophages and NK cells and sustains tissue inflammation. 4) Anti-CTLA-4 complement activation: anti-CTLA-4 antibodies bind CTLA-4 expressed on normal cells (e.g., pituitary cells) and trigger complement-dependent cytotoxicity and localized inflammation, a mechanism implicated in CTLA-4-related hypophysitis. 5) Innate immune activation: activated macrophages and myeloid cells interact with T cells to amplify cytokine release and propagate autoinflammatory reactions, contributing to tissue injury such as ICI-induced hepatitis and colitis. CTLA-4, cytotoxic T-lymphocyte associated protein 4; Th, T helper; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor-alpha; IL, interleukin; NK cells, natural killer cells; ICI, immune checkpoint inhibitor.

Figure 3.

Overview of management strategies for immune-related adverse events (irAEs). General management of irAEs begins with corticosteroids, such as prednisone at a dose of 0.5-2.0 mg/kg/day (either orally or intravenously) or methylprednisolone at a dose of 1-2 mg/kg/day intravenously for grade 3-4 events. Life-threatening irAEs include hemophagocytic lymphohistiocytosis, myocarditis, fulminant hepatitis (acute liver failure), encephalitis, Guillain-Barré syndrome (GBS), myasthenia gravis (MG), giant cell arteritis, and acute respiratory distress syndrome. For these conditions, a pulse dose of methylprednisolone is recommended: 500-1,000 mg intravenously daily for 3-5 days. Pulse-dose methylprednisolone therapy generally follows NCCN or ESMO guideline recommendations (continuous yellow lines). However, fulminant hepatitis (acute liver failure) is not included in these guideline-based indications and therefore requires particular caution (dashed yellow line). Steroid-refractory cases should be treated with organ-specific immunosuppressive agents, such as infliximab (anti-TNF) or vedolizumab (anti-α4β7 integrin) for colitis, MMF (antimetabolite) or tocilizumab (anti-IL-6R) for hepatitis, and tocilizumab (anti-IL-6R) for pneumonitis, myocarditis, or skin rash. Red X indicates agents that should be avoided or used with caution in certain irAEs (e.g., infliximab in hepatitis, tocilizumab in colitis due to risk of gastrointestinal perforation). PO, oral; IV, intravenous; TNF, tumor necrosis factor; IL, interleukin; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; MMF, mycophenolate mofetil; NCCN, National Comprehensive Cancer Network; ESMO, European Society for Medical Oncology.

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Figure & Data

References

Citations

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