Immune Checkpoint Inhibitor-Induced Hepatotoxicity
Summary
Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by unleashing cytotoxic T-cell responses against tumours. However, disruption of immunological tolerance in the liver gives rise to hepatotoxicity, manifesting as hepatocellular, cholestatic or mixed injury patterns. Clinically, liver enzyme elevations occur in up to a quarter of treated patients, with combination regimens and anti-CTLA-4 agents generally carrying higher risk than PD-1/PD-L1 monotherapy. Histologically, affected livers show mononuclear infiltration—often rich in CD8+ T cells—and variable bile duct injury. Recent preclinical work has highlighted roles for NLRP3 inflammasome activation in hepatocytes and cross-talk between innate macrophages, Kupffer cells and adaptive T-cell subsets as key drivers of tissue damage. Management relies primarily on corticosteroids and, in refractory cases, secondary immunosuppressants, with treatment interruption often necessary. Standardised grading systems and timely liver biopsy guide therapeutic decisions, while efforts to disentangle anti-tumour efficacy from immune-related toxicity continue to inform rechallenge protocols. Given the expanding indications for ICIs, understanding the mechanisms, risk factors and optimal management of hepatotoxicity is critical to safeguard global patient outcomes without compromising anticancer benefit.
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Immune Checkpoint Inhibitor-Induced Hepatotoxicity publication trend
The graph below shows the total number of articles in immune checkpoint inhibitor-induced hepatotoxicity across all publications each year (not limited to Nature Index journals).
Technical terms
Immune checkpoint inhibitors: Monoclonal antibodies that block inhibitory pathways in T cells to enhance antitumour immunity.
Hepatotoxicity: Liver injury resulting from drug-induced immune-mediated or direct cytotoxic effects.
Inflammasome: A multiprotein complex that activates inflammatory caspases and cytokines in innate immunity.
Apoptosis: Programmed cell death characterised by caspase activation and cellular fragmentation.
Pyroptosis: Inflammatory form of programmed cell death mediated by Gasdermin-D and caspase-1.
Cholestatic profile: Pattern of liver injury marked by elevated bile-related enzymes and impaired bile flow.
Hepatocellular profile: Liver injury pattern dominated by elevated aminotransferases reflecting direct hepatocyte damage.
Kupffer cells: Liver-resident macrophages involved in clearance of pathogens and modulation of immune responses.
References
- Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors. Cell Death & Disease (2024).
- Cholangitis Induced by Immune Checkpoint Inhibitors: Analysis of Pharmacovigilance Data. Clinical Gastroenterology and Hepatology (2023).
- Immune-mediated hepatitis induced by immune checkpoint inhibitors: Current updates and future perspectives. Frontiers in Pharmacology (2023).
- Histologic patterns of liver injury induced by anti-PD-1 therapy. Gastroenterology Report (2019).
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