The double-edged sword of PD‑1/PD‑L1 blockade: Bridging hepatocellular carcinoma to liver transplantation while...

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed hepatocellular carcinoma (HCC) treatment, with frontline combination regimens now reaching 25-35% objective response rates. This has fueled interest in using ICIs as a bridge before liver transplantation (LT), despite an inherent conflict: the same pathway deriving antitumor immunity also maintains graft tolerance, so blocking it risks setting off graft-destructive alloreactivity. This review focuses on pre-transplant bridging, though post-transplant and other transplant contexts are drawn on where they add mechanistic insight. We synthetize the evidence on ICI-based bridging to LT in HCC. Reported series show 3-year intention-to-treat survival nearing 71%, with about a third of patients achieving pathologic complete response. Acute rejection after transplant, though, varies widely, from 17% up to over 56%. Mechanistically, PD-1/PD-L1 blockade lifts the brake on donor-reactive CD8 + T-cell expansion and throws off regulatory T-cell balance in the graft. Shorter washout periods are consistently tied to higher rejection risk, which drops below 10% past 50 days and nears baseline around 90 days, a pattern that tracks more closely with receptor occupancy than with serum drug half-life. Perioperative immunosuppression needs careful tailoring, and mTOR inhibitor-based maintenance is emerging as preferred, given its antiproliferative effect and its tendency to spare Tregs. Biomarkers spanning multiple platforms, such as donor-derived cell-free DNA and liquid biopsy, could help tailor candidate selection and post-transplant monitoring. Until prospective trials pin down clear thresholds, clinicians will need to weigh oncologic risk against immunologic risk through multidisciplinary collaboration at centers with real experience in this space.