JHEP reports : innovation in hepatology · 2026
Combined anti-PD-1 with irreversible electroporation relieves immunosuppression and reduces hepatocellular carcinoma regrowth.
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Huo Jihui, Wang Lina, Lei Kai, Luo Weishan, Wang Zongren, Zhu Hongtao, Zheng Gaomin, Kang Youmei, Huang Wenjie, Ren Xiaoxue, Hou Yingdong, Liang Cong, Yang Tao, Lin Manxia, Li Xiaoxing, Peng Sui, Kuang Ming, Xiao Han, Chen Shuling, Dai Zihao
Аннотация
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: IRE initially inhibited HCC growth, but tumors rapidly regrew by day 14 after ablation, with increased Ly6G+ Polymorphonuclear (PMN) Myeloid-Derived Suppressor Cells (MDSCs) infiltration and CD8+ T cell exhaustion. In patient-derived HCC organoids, IRE-induced CD8+ T cell cytotoxicity was suppressed by MDSCs. Ly6G antibody-mediated PMN-MDSC 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 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 prospecitve 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 (TIME). 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.
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: IRE initially inhibited HCC growth, but tumors rapidly regrew by day 14 after ablation, with increased Ly6G+ Polymorphonuclear (PMN) Myeloid-Derived Suppressor Cells (MDSCs) infiltration and CD8+ T cell exhaustion. In patient-derived HCC organoids, IRE-induced CD8+ T cell cytotoxicity was suppressed by MDSCs. Ly6G antibody-mediated PMN-MDSC 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 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 prospecitve 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 (TIME). 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.