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<p>Hepatocellular carcinoma (HCC) remains a major cause of cancer-related death worldwide, with limited efficacy of current immunotherapies due to an immunosuppressive tumor microenvironment and dysfunctional CD8⁺ tumor-infiltrating lymphocytes (TILs). Among these, PD-1⁺CD25⁺ CD8⁺ T cells represent a tumor-reactive subset linked to IL-2 responsiveness and favorable responses to PD-1 blockade. In this study, we integrated single-cell and spatial transcriptomics with clinical immunotherapy cohort analyses to characterize the phenotype and function of PD-1⁺CD25⁺ CD8⁺ TILs in human HCC. To therapeutically exploit this subset, we engineered IL-2(N88D)/CD25 fusion proteins with trimeric receptor bias, selectively promoting the expansion of PD-1⁺CD25⁺ CD8⁺ T cells. These constructs were tested in multiple murine HCC models, including orthotopic and hydrodynamic tail vein injection systems. PD-1⁺CD25⁺ CD8⁺ TILs were enriched in HCC tumors, particularly in immunotherapy responders, and exhibited enhanced tumor reactivity and neoantigen specificity. Treatment with IL-2/CD25 led to increased CD8⁺ T cell infiltration and delayed tumor progression with minimal toxicity, while the IL-2(N88D)/CD25 variant further boosted infiltration, activation, and survival outcomes. These findings highlight the therapeutic potential of selectively activating antigen-specific CD8⁺ T cells via IL-2(N88D)/CD25 fusion proteins, offering a promising strategy for improving HCC immunotherapy.</p>

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IL-2(N88D)/CD25 Fusion Protein Enhances Expansion of Antigen-Specific CD8⁺ T Cells to Suppress Hepatocellular Carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Nan Xu,
  • Yisu Song,
  • Zhaofeng Xiao,
  • Yiyuan Chen,
  • Lijun Meng,
  • Zhengxing Lian,
  • Tianwei Chen,
  • Zhoucheng Wang,
  • Xiao Xu,
  • Hongda Ding,
  • Shuai Wang,
  • Jian Wu

摘要

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related death worldwide, with limited efficacy of current immunotherapies due to an immunosuppressive tumor microenvironment and dysfunctional CD8⁺ tumor-infiltrating lymphocytes (TILs). Among these, PD-1⁺CD25⁺ CD8⁺ T cells represent a tumor-reactive subset linked to IL-2 responsiveness and favorable responses to PD-1 blockade. In this study, we integrated single-cell and spatial transcriptomics with clinical immunotherapy cohort analyses to characterize the phenotype and function of PD-1⁺CD25⁺ CD8⁺ TILs in human HCC. To therapeutically exploit this subset, we engineered IL-2(N88D)/CD25 fusion proteins with trimeric receptor bias, selectively promoting the expansion of PD-1⁺CD25⁺ CD8⁺ T cells. These constructs were tested in multiple murine HCC models, including orthotopic and hydrodynamic tail vein injection systems. PD-1⁺CD25⁺ CD8⁺ TILs were enriched in HCC tumors, particularly in immunotherapy responders, and exhibited enhanced tumor reactivity and neoantigen specificity. Treatment with IL-2/CD25 led to increased CD8⁺ T cell infiltration and delayed tumor progression with minimal toxicity, while the IL-2(N88D)/CD25 variant further boosted infiltration, activation, and survival outcomes. These findings highlight the therapeutic potential of selectively activating antigen-specific CD8⁺ T cells via IL-2(N88D)/CD25 fusion proteins, offering a promising strategy for improving HCC immunotherapy.