Background aims: Immune checkpoint inhibitors (ICI) have transformed the management of advanced hepatocellular carcinoma (HCC), yet their integration in the perioperative setting remains insufficiently explored. This study aims to investigate the effect of hepatectomy on the tumor microenvironment and assess whether neoadjuvant or adjuvant anti-PD-1 therapy offers improved therapeutic outcomes.

Methods: Using a murine orthotopic HCC model, a non-curative partial hepatectomy was performed, removing a non-tumor-bearing lobe with anti-PD-1 administered as neoadjuvant or adjuvant therapy. In a separate experiment, curative hepatectomy (resection of the tumor-bearing lobe) was performed to evaluate recurrence and survival.

Results: Anti-PD-1 therapy significantly reduced tumor growth in non-surgical settings (p=0.0094), but its efficacy was lost in the adjuvant setting. This loss correlates with reduced infiltration of effector memory CD103⁺CD8⁺ T cells, increased expression of exhaustion markers (TIM-3, LAG-3), and accumulation of myeloid-derived suppressor cells (MDSC). MDSC depletion at the time of surgery improved adjuvant efficacy (p=0.0084), and delaying adjuvant ICI partially rescued responses, indicating a temporary postoperative immunosuppressive window. By contrast, neoadjuvant anti-PD-1 therapy significantly reduced tumor burden (p=0.0005), enhanced immune cell infiltration, and increased the expression of key activation markers on CD8+ cells (Tbx21, Gzma, Cxcr6, Cd69). Moreover, neoadjuvant treatment significantly reduced recurrence rates compared to sham treatment (35% vs. 68%, p=0.0405) and improved survival (p=0.0373), which was not achieved with adjuvant therapy.

Conclusions: Partial hepatectomy disrupts antitumor immunity and limits adjuvant ICI efficacy. Neoadjuvant anti-PD-1 immunotherapy offers a superior strategy compared to adjuvant immunotherapy in enhancing immune responses and reducing HCC recurrence.