Combined anti-PD-1 with irreversible electroporation relieves immunosuppression and reduces hepatocellular carcinoma regrowth

作者：Jihui Huo, Lina Wang, Kai Lei, Weishan Luo, Zongren Wang, Hongtao Zhu, Gaomin Zheng, Youmei Kang, Wenjie Huang, Xinxin Ren, Yingdong Hou, Cong Liang, Tao Yang, Manxia Lin, Xiaoxing Li, Sui Peng, Ming Kuang, Han Xiao, Shuling Chen, Zihao Dai · 发表于：JHEP Reports · 年份：2026 · DOI：10.1016/j.jhepr.2026.101977 · 研究领域：Microbial Inactivation Methods、Endoplasmic Reticulum Stress and Disease、Toxin Mechanisms and Immunotoxins

BACKGROUND & AIMS: Local ablation triggers anti-tumor response and is regarded as an encouraging treatment combined with immunotherapy for hepatocellular carcinoma (HCC). Irreversible electroporation (IRE) is a novel ablative technique eliminating tumor cells by electroporation, however, the characteristics of IRE-induced immune microenvironment and underlying mechanism remain unclear. METHODS: We developed an orthotopic immunocompetent HCC mouse model and performed incomplete IRE-ablation. The post-IRE immune microenvironment was characterized by RNA sequencing, single-cell RNA sequencing, flow cytometry, and multiplex immunofluorescence. Cytokine-chemokine array and organoid-immune cell co-culture were used to investigate the functions and underlying mechanism. The combination therapy of IRE and anti-PD-1 was examined for HCC treatment in mice. RESULTS: T cells exhaustion. Combined anti-PD-1 and IRE reduced tumor burden by 84.3% compared with IRE alone (0.22±0.08 vs 1.43±0.13 g, p<0.01), prolonged survival (day-60 survival: 93.33% vs 40%, p<0.001), and induced long-term anti-tumor immunity in mice. Four unresectable recurrent HCC patients treated with IRE plus anti-PD-1 therapy showed improved recurrence-free time than patients receiving IRE alone. CONCLUSIONS: PMN-MDSCs mediated immunosuppression that promoted HCC regrowth after incomplete IRE ablation. Combining anti-PD-1 therapy is a promising approach to eliminate post-ablation residual HCC, supporting evaluation in pro...