Authors
Nan Xu, Yisu Song, Zhaofeng Xiao, Yiyuan Chen, Lijun Meng, Zhengxing Lian, Tianwei Chen, Zhoucheng Wang, Xiao Xu, Hongda Ding, Shuai Wang, Jian Wu
Published in
Communications biology. Jul 20, 2026. Epub Jul 20, 2026.
Abstract
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.
PMID:
42477428
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.
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