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

@article{huo2026combined,
  title = {{Combined anti-PD-1 with irreversible electroporation relieves immunosuppression and reduces hepatocellular carcinoma regrowth}},
  author = {Jihui Huo and Lina Wang and Kai Lei and Weishan Luo and Zongren Wang and Hongtao Zhu and Gaomin Zheng and Youmei Kang and Wenjie Huang and Xiaoxue Ren and Yingdong Hou and Cong Liang and Tao Yang and Manxia Lin and Xiaoxing Li and Sui Peng and Ming Kuang and Han Xiao and Shuling Chen and Zihao Dai},
  journal = {JHEP Reports},
  year = {2026},
  month = aug,
  doi = {10.1016/j.jhepr.2026.101977},
  url = {https://doi.org/10.1016/j.jhepr.2026.101977},
  note = {CC BY-NC-ND 4.0},
}

TY  - JOUR
TI  - Combined anti-PD-1 with irreversible electroporation relieves immunosuppression and reduces hepatocellular carcinoma regrowth
AU  - Jihui Huo
AU  - Lina Wang
AU  - Kai Lei
AU  - Weishan Luo
AU  - Zongren Wang
AU  - Hongtao Zhu
AU  - Gaomin Zheng
AU  - Youmei Kang
AU  - Wenjie Huang
AU  - Xiaoxue Ren
AU  - Yingdong Hou
AU  - Cong Liang
AU  - Tao Yang
AU  - Manxia Lin
AU  - Xiaoxing Li
AU  - Sui Peng
AU  - Ming Kuang
AU  - Han Xiao
AU  - Shuling Chen
AU  - Zihao Dai
PY  - 2026
DA  - 2026/08/03
JO  - JHEP Reports
DO  - 10.1016/j.jhepr.2026.101977
UR  - https://doi.org/10.1016/j.jhepr.2026.101977
AB  - Background & Aims: Local ablation triggers an antitumor 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-programmed cell death protein 1 (PD-1) was examined for HCC treatment in mice.  Results: IRE initially inhibited HCC growth, but tumors rapidly regrew by day 14 after ablation, with increased Ly6G+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) infiltration and CD8+ T-cell exhaustion. In patient-derived HCC organoids, IRE-induced CD8+ T-cell cytotoxicity was suppressed by myeloid-derived suppressor cells (MDSCs). Ly6G antibody-mediated PMN-MDSCs depletion repressed HCC regrowth after IRE-ablation in vivo (1.29 ± 0.12 vs 0.49 ± 0.09 g, p <0.001). Mechanistically, HCC cells degraded CXCL10 mRNA via YTH N6-methyladenosine RNA binding protein F2 (YTHDF2), which activated MDSCs that led to CD8+ T-cell exhaustion. Combined anti-PD-1 and IRE reduced tumor burden by 84.6% compared with IRE alone (0.22 ± 0.08 vs 1.43 ± 0.13 g, p <0.01), prolonged survival (40-day survival: 60% vs 6.7%, p <0.001), and induced long-term antitumor immunity in mice. Four patients with unresectable recurrent HCC 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 prospective clinical trials.  Impact and implications: Post-ablation recurrence remains a major challenge in HCC. Here, we show that although IRE initially activates CD8+ T cells but subsequently promotes PMN-MDSCs activation and CD8+ T-cell exhaustion through YTHDF2-mediated CXCL10 mRNA degradation, resulting in a suppressive tumor immune microenvironment. These findings identify a previously unrecognized mechanism of post-IRE tumor regrowth and provide a rationale for early combination with anti-PD-1 therapy. Although further prospective clinical validation is required, this work suggests that monitoring post-ablation immune changes and applying rational immunotherapy combinations may help optimize treatment strategies for patients with HCC undergoing local ablation.
SN  - 2589-5559
ER  -