Hepatotoxicity in the Era of Precision Medicine: Toxicological Mechanisms and Management of Immune and Cell Therapy-Induced Liver Injury.

Abstract

Immune checkpoint inhibitors and adoptive cell therapies have revolutionized cancer treatment, yet their success is accompanied by immune-related hepatotoxicity that can range from asymptomatic enzyme elevation to life-threatening liver failure. Unlike conventional drug-induced liver injury, immune-mediated hepatotoxicity arises from complex, therapy-specific mechanisms that remain incompletely understood, creating critical knowledge gaps in risk prediction and prevention. This review incorporates current evidence on the clinical presentation, mechanistic pathways, and risk factors underlying hepatotoxicity across major immune and cell therapy platforms, with emphasis on translating mechanistic insights into actionable management strategies. We systematically examine hepatotoxicity patterns for immune checkpoint inhibitors, CAR-T cell therapies, bispecific T-cell engagers, and tumor-infiltrating lymphocyte therapy, integrating clinical trial data, real-world evidence, and mechanistic studies. Our analysis shows distinct injury mechanisms: T-cell-mediated hepatocyte destruction following checkpoint blockade, cytokine-driven bystander injury during cytokine release syndrome, and emerging on-target/off-tumor toxicity from engineered lymphocytes. Critical risk modifiers include pre-existing liver disease, concomitant hepatotoxic medications, gut microbiome dysbiosis from antibiotic exposure, and host pharmacogenomic variation. We propose three priority research directions: development of predictive biomarkers enabling pretreatment risk stratification, microbiome-directed interventions to preserve hepatic immune tolerance, and implementation of Safety-by-Design engineering strategies that integrate hepatotoxicity prevention into therapeutic design. This review provides a mechanistic framework for transitioning from reactive toxicity management to predictive, personalized prevention, essential for maximizing the therapeutic potential of immune and cell therapies while protecting patient safety in this rapidly expanding treatment landscape.