Scholarlink

Background <p>Hepatocellular carcinoma (HCC) is a global health challenge, with limited treatment options for advanced-stage patients. Although recent approvals of targeted therapies and immune checkpoint inhibitors (ICIs) have expanded the therapeutic landscape, their clinical benefits are often constrained by modest response rates and acquired resistance. Despite ongoing efforts to identify new therapeutic targets, only few inhibitors have progressed to clinical trials, benefiting a small subset of patients. These limitations underscore the need for more effective therapeutic strategies.</p> Methods <p>We integrated data from DepMap and TCGA to identify HCC-specific vulnerabilities. A kinome-wide CRISPR screen validated essential targets. Pharmacological inhibition (AZD1152) and genetic knockout of Aurora B (AURKB) were employed for functional validation. Senescence was assessed via SA-β-gal staining, transcriptomics, and SASP analysis. Immune interactions were evaluated using co-culture assays with T cells and flow cytometry for MHC I and immune markers. In vivo efficacy was tested in immunocompetent murine HCC models.</p> Results <p>Aurora B was identified as a top candidate essential for HCC survival, overexpressed in tumors, and correlated with poor prognosis. A kinome-wide CRISPR screen further confirmed its essential role in HCC cell survival. Pharmacologic inhibition or genetic knockout of Aurora B markedly suppressed proliferation of HCC cells and induced robust cellular senescence, characterized by cell-cycle arrest, DNA damage, and SASP. These senescent cells exhibited heightened susceptibility to T-cell-mediated cytotoxicity, associated with increased immunoproteasome activity and upregulated MHC I expression. Co-culture assays revealed that senescent tumor cells promoted interferon-γ production and enhanced cytotoxicity in CD8⁺ T cells as well as PD-1 expression. In both in vitro and in vivo models, combining Aurora B inhibition with anti-PD-1 therapy markedly suppressed tumor growth.</p> Conclusion <p>This study identifies Aurora B as a therapeutically actionable vulnerability in HCC, whose inhibition induces senescence and enhances tumor immunogenicity. The combination of Aurora B inhibitor with anti-PD-1 therapy yields synergistic anti-tumor effects, supporting its potential as a promising strategy to improve immunotherapy outcomes in HCC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Inhibition of Aurora B induces senescence and potentiates immunotherapy in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月22日

查看全文
  • Shanshan Wu,
  • Hui Wang,
  • Chune Yu,
  • Chen Yang,
  • Xifu Cheng,
  • Long Liao,
  • Ying Cao,
  • Wenxin Qin,
  • Xuhui Ma

摘要

Background

Hepatocellular carcinoma (HCC) is a global health challenge, with limited treatment options for advanced-stage patients. Although recent approvals of targeted therapies and immune checkpoint inhibitors (ICIs) have expanded the therapeutic landscape, their clinical benefits are often constrained by modest response rates and acquired resistance. Despite ongoing efforts to identify new therapeutic targets, only few inhibitors have progressed to clinical trials, benefiting a small subset of patients. These limitations underscore the need for more effective therapeutic strategies.

Methods

We integrated data from DepMap and TCGA to identify HCC-specific vulnerabilities. A kinome-wide CRISPR screen validated essential targets. Pharmacological inhibition (AZD1152) and genetic knockout of Aurora B (AURKB) were employed for functional validation. Senescence was assessed via SA-β-gal staining, transcriptomics, and SASP analysis. Immune interactions were evaluated using co-culture assays with T cells and flow cytometry for MHC I and immune markers. In vivo efficacy was tested in immunocompetent murine HCC models.

Results

Aurora B was identified as a top candidate essential for HCC survival, overexpressed in tumors, and correlated with poor prognosis. A kinome-wide CRISPR screen further confirmed its essential role in HCC cell survival. Pharmacologic inhibition or genetic knockout of Aurora B markedly suppressed proliferation of HCC cells and induced robust cellular senescence, characterized by cell-cycle arrest, DNA damage, and SASP. These senescent cells exhibited heightened susceptibility to T-cell-mediated cytotoxicity, associated with increased immunoproteasome activity and upregulated MHC I expression. Co-culture assays revealed that senescent tumor cells promoted interferon-γ production and enhanced cytotoxicity in CD8⁺ T cells as well as PD-1 expression. In both in vitro and in vivo models, combining Aurora B inhibition with anti-PD-1 therapy markedly suppressed tumor growth.

Conclusion

This study identifies Aurora B as a therapeutically actionable vulnerability in HCC, whose inhibition induces senescence and enhances tumor immunogenicity. The combination of Aurora B inhibitor with anti-PD-1 therapy yields synergistic anti-tumor effects, supporting its potential as a promising strategy to improve immunotherapy outcomes in HCC.