Advances in mechanistic investigation and treatment of steroid-refractory ICI-induced liver injury.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer immunotherapy, significantly improving patient survival. However, their use is frequently associated with immune-related adverse events, including immune checkpoint inhibitor-induced liver injury (ICI-DILI), which poses substantial clinical challenges. While corticosteroid therapy remains the primary treatment for ICI-DILI, many patients with steroid-refractory cases, especially those involving non-hepatocellular injury, exhibit resistance to standard therapies. Emerging evidence suggests that factors such as MDR1 expression, PD-L1 (Programmed cell death ligand (1)) and PD-L2 (Programmed cell death ligand (2)) expression levels, and liver injury patterns contribute to steroid resistance, highlighting the need for alternative treatment strategies. Recent advancements in therapeutic research have identified promising second-line treatments, including immunosuppressants (tacrolimus, cyclosporine A, mycophenolate mofetil, and azathioprine), monoclonal antibodies (infliximab and tocilizumab), anti-thymocyte globulin, intravenous immunoglobulin, ursodeoxycholic acid for cholestatic cases, and blood purification techniques. These innovations offer new possibilities for managing steroid-refractory ICI-DILI. This review also explores critical gaps in the field, including the lack of reliable diagnostic criteria and biomarkers for hormone-refractory ICI-DILI. Furthermore, we discuss the development of novel therapies informed by evolving insights into the condition's pathogenesis and the feasibility of reintroducing ICIs after ICI-DILI resolution. These advancements mark significant progress in optimizing patient outcomes and advancing the mechanistic understanding of ICI-DILI.