Less is more: A single-dose, non-waiting neoadjuvant immunotherapy strategy for hepatocellular carcinoma

Abstract

Neoadjuvant immune checkpoint inhibitors (ICIs) are increasingly being explored in multiple solid tumors, conventionally delivered as multi-cycle preoperative regimens or as part of perioperative strategies that include postoperative therapy. However, directly adopting these approaches presents distinct challenges in hepatocellular carcinoma (HCC). In the Asia-Pacific region, curative surgery remains feasible even for patients with a large tumor burden. These patients may derive the greatest benefit from neoadjuvant immunotherapy due to their high risk of recurrence, yet they also face the narrowest surgical window. Disease progression during prolonged neoadjuvant treatment period can easily hinder resectability. Additionally, intensive neoadjuvant treatment-related adverse events, especially hepatotoxicity, may delay surgery. A HCC-specific approach that prioritizes surgical feasibility while preserving benefit of immunotherapy is needed.

Recent pharmacodynamic and clinical evidence indicates that a single dose of programmed cell death-1 (PD-1) or its ligand (PD-L1) antibody can rapidly achieve near-complete receptor occupancy and early T-cell activation. Receptor occupancy can be sustained in the early postoperative period. This provides a strong scientific rationale for a single-dose, non-waiting neoadjuvant strategy, in which anti-PD-1 or anti-PD-L1 is administered shortly before surgery without delaying resection. Such an approach may allow early antitumor immune activation while minimizing treatment-related adverse events (TRAEs), preserving surgical feasibility and reducing logistical complexity. It may enhance acceptance among patients and surgeons. Future neoadjuvant trials in HCC should consider adopting this “less is more” paradigm to investigate whether abbreviated neoadjuvant immunotherapy can safely translate immunologic activation into meaningful clinical benefit, as measured by event-free survival.