Hepatectomy alters adjuvant anti–PD-1 action in a mouse model of HCC but does not compromise neoadjuvant efficacy

Background and Aims: Immune checkpoint inhibitors have transformed the management of advanced 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 (programmed cell death protein 1) therapy offers improved therapeutic outcomes. Approach and Results: Using a murine orthotopic HCC model, a noncurative 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. Anti–PD-1 therapy significantly reduced tumor growth in nonsurgical 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 and LAG-3), and accumulation of myeloid-derived suppressor cells. Myeloid-derived suppressor cell depletion at the time of surgery improved adjuvant efficacy ( p =0.0084), and delaying adjuvant immune checkpoint inhibitor 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, and Cd69). Moreover, neoadjuvant treatment significantly reduced recurrence rates compared with 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 immune checkpoint inhibitor efficacy. Neoadjuvant anti–PD-1 immunotherapy offers a superior strategy compared with adjuvant immunotherapy in enhancing immune responses and reducing HCC recurrence.