Objective  To investigate the relationship between pre-liver transplantation plasma soluble programmed cell death protein 1 (sPD-1) levels and prognosis in hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICI).

Methods  A total of 38 HCC liver transplant recipients who received ICI treatment at Beijing Tsinghua Changgung Hospital from January 2021 to February 2024 were included in the study. The use of ICI drugs was reviewed, and the clinical and pathological characteristics of patients with and without postoperative HCC recurrence were compared. Kaplan-Meier analysis was used to evaluate postoperative survival. Pre-transplant plasma samples were collected from patients treated with ICI, and the sPD-1 levels were measured using enzyme-linked immunosorbent assay. Receiver operating characteristic curves were plotted to explore the relationship between sPD-1 expression and clinical pathological features and to analyze the prognosis. The effects of different preoperative ICI discontinuation times on sPD-1 expression were also compared.

Results  Among the patients, 28 (74%) received anti-programmed cell death protein 1 (PD-1) monoclonal antibodies, 9 (24%) received anti-programmed cell death protein ligand 1 (PD-L1) monoclonal antibodies, and 1 (3%) received bispecific antibodies. Patients were grouped based on whether they had HCC recurrence within 1 year after surgery. Significant differences were found between the two groups in preoperative alpha-fetoprotein levels, tumor number, maximum tumor diameter, capsular invasion, differentiation grade, Ki67 index, Milan criteria, University of California San Francisco criteria, metastatic staging, postoperative hospital stay and total hospital stay (all P<0.05). The median pre-transplant plasma sPD-1 level was 902 (318, 4 406) pg/mL, and the sPD-1 level was higher in the recurrence group than in the non-recurrence group (P<0.05). Using 2 073 pg/mL as the cut-off value, patients were divided into high and low sPD-1 level groups. Significant differences were found between the two groups in tumor number, postoperative hospital stay and total hospital stay (all P<0.05). Kaplan-Meier analysis showed that the disease-free survival rate was lower in the high sPD-1 level group than in the low sPD-1 level group (P=0.004), while the overall survival rate did not differ significantly between the two groups (P=0.381). In addition, patients who discontinued ICI treatment less than 5 half-lives before surgery had higher sPD-1 levels than those who discontinued ICI treatment for at least 5 half-lives before surgery.

Conclusions  Pre-transplant plasma sPD-1 levels are closely related to prognosis and may reflect the dynamic changes in the immune microenvironment. For patients with high pre-transplant plasma sPD-1 levels, the indications for liver transplantation should be carefully evaluated, and postoperative management and follow-up should be strengthened. Early intervention should be provided to improve patients' quality of life and prolong their survival.