Blood Marker Soluble PD-1 Flags Cancer Return After Liver Transplant in Immunotherapy Patients

Liver transplantation offers the best chance of cure for patients with hepatocellular carcinoma whose tumors are complicated by cirrhosis, but a new clinical dilemma is reshaping the field. Immune checkpoint inhibitors, the antibody drugs that unleash T cells against tumors, are increasingly used before transplantation to bridge or downstage liver cancer, yet a subset of patients still sees their cancer return after the new liver is in place. Researchers in Beijing now report that a simple blood measurement taken the day before surgery may identify which of these patients face the highest risk.

The study, published in Frontiers in Oncology by Lizhen Zhu of Qinghai University Affiliated Hospital and colleagues at Beijing Tsinghua Changgung Hospital, focused on a circulating molecule called soluble programmed death-1, or sPD-1. Unlike the membrane-bound PD-1 receptor that checkpoint inhibitors block, sPD-1 is a free-floating isoform generated by proteolytic cleavage or alternative splicing. It is thought to reflect peripheral T-cell activation, and previous work has tied it to prognosis in several solid tumors, though results have varied widely by tumor type, regimen, and assay. Whether it meant anything for patients heading into transplantation after immunotherapy was unknown.

To find out, the team measured pretransplant plasma sPD-1 and soluble PD-L1 with validated enzyme-linked immunosorbent assays in 105 liver transplant recipients with hepatocellular carcinoma. Fifty-one had received immune checkpoint inhibitors before surgery, while 54 had not, including 18 who went straight to transplant and 36 who received non-immunotherapy bridging treatment. Blood was drawn one day before transplantation, processed by centrifugation, stored at minus 80 degrees Celsius in a centralized biobank, and assayed in duplicate by laboratory staff blinded to clinical outcomes. The primary endpoint was two-year recurrence-free survival.

The numbers were striking. Patients treated with checkpoint inhibitors had markedly higher pretransplant sPD-1 than those without such exposure, a difference that was highly significant. Within the immunotherapy group itself, the pattern became even more consequential: the 21 patients whose cancer returned after transplantation had far higher sPD-1 concentrations than the 30 who stayed recurrence-free, while soluble PD-L1 showed no such separation. Using an exploratory cutoff of 2,073 picograms per milliliter, derived from the study cohort itself with a receiver operating characteristic analysis, high sPD-1 was associated with a two-year recurrence-free survival of just 7.7 percent, compared with 76.3 percent among patients below the threshold.

Statistical modeling reinforced the signal. Analyzed as a continuous variable, each doubling of pretransplant sPD-1 was associated with a 51 percent increase in the hazard of recurrence in unadjusted Cox regression. Crucially, the association survived adjustment for alpha-fetoprotein, the standard tumor marker, as well as tumor number and maximum tumor diameter, with an adjusted hazard ratio of 1.51. In separate multivariable analysis, both AFP and sPD-1 remained independently linked to recurrence, and a parsimonious model combining the two achieved an optimism-corrected concordance index of 0.736 after bootstrap validation, suggesting modest but real discriminative ability.

Perhaps most intriguing was where the signal appeared. The association held among patients whose scans showed a response by modified RECIST criteria, among patients whose explanted livers showed no microvascular invasion, and among patients with AFP at or below 400 nanograms per milliliter, the conventional low-risk threshold. In that final subgroup, high sPD-1 still stratified survival, with a hazard ratio of 4.15. The implication is that soluble PD-1 may capture systemic immune information that standard tumor-burden measures, radiological response, and pathology all miss, offering a glimpse of residual risk that the existing toolkit cannot see.

The investigators also probed whether the marker was simply an artifact of treatment timing. Neither the number of immunotherapy cycles nor the interval between the last drug dose and blood sampling, which had a median of 65.5 days, correlated significantly with sPD-1 levels. Acute cellular rejection, the safety concern that has dominated prior studies of immunotherapy before transplantation, occurred in 15.7 percent of the immunotherapy group and was managed successfully in every case, and sPD-1 showed no association with rejection episodes.

Still, the authors are careful about scope. The study is a single-center retrospective cohort with only 21 recurrence events in the immunotherapy group, the cutoff was derived and tested in the same patients, and microvascular invasion could only be assessed after surgery. Formal mechanistic work, including immune-cell profiling and tumor immunophenotyping, was outside its reach, and the researchers cannot rule out assay interference from residual therapeutic antibodies, a known hazard when measuring soluble checkpoint molecules in treated patients. They recommend future studies incorporate drug-specific interference testing and standardized sampling windows.

Those caveats notwithstanding, the work signals a shift in how clinicians think about immunotherapy before liver transplantation. The conversation has moved beyond allograft safety toward predicting tumor recurrence, and a plasma biomarker drawn the day before surgery fits neatly into that vision. Soluble PD-1 is not ready for the clinic, the authors stress, and independent validation in larger external cohorts is required. But if the finding holds, a routine blood test could soon help decide which patients getting checkpoint inhibitors before a new liver are truly cured, and which need closer surveillance after the operation.

Subject of Research: Soluble PD-1 as a pretransplant biomarker predicting recurrence after liver transplantation in immunotherapy-treated hepatocellular carcinoma

Article Title: Pretransplant plasma soluble PD-1 and recurrence after liver transplantation in ICI-treated hepatocellular carcinoma: an exploratory biomarker study

Article References: Zhu, L., Wang, R., Shu, W., Gao, Y., Zhang, G., Zhao, W., Hou, Y., & Lu, Q. (2026). Pretransplant plasma soluble PD-1 and recurrence after liver transplantation in ICI-treated hepatocellular carcinoma: an exploratory biomarker study. Frontiers in Oncology, 16, Article 1944586. https://doi.org/10.3389/fonc.2026.1944586

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1944586

Keywords: hepatocellular carcinoma, liver transplantation, immune checkpoint inhibitors, soluble PD-1, biomarker, cancer recurrence, AFP, microvascular invasion, recurrence-free survival, ELISA, transplant oncology, prognosis