Scholarlink

Background <p>Checkpoint inhibitors have revolutionized hepatocellular carcinoma (HCC) treatment, yet their efficacy remains limited in advanced stages, with suboptimal objective response rates. Growth differentiation factor 15 (GDF15), a dual-functional cytokine implicated in tumor progression and immunosuppression, represents a promising therapeutic target. This study aims to develop a novel GDF15-targeted strategy to improve HCC management and synergize with PD-1 blockade.</p> Methods <p>GFRAL-Fc fusion proteins were generated by fusing the extracellular domain of GFRAL with IgG1 Fc. The anti-tumor efficacy and the anti-cachexia ability of GFRAL-Fc was evaluated in a spontaneous HCC model on GDF15 humanized mice. Additionally, the half-life and drug safety were evaluated in mice. To investigate the underlying mechanisms, a CyTOF analysis was utilized to analysis the immunoregulation effects of GFRAL-Fc within HCC. Finally, the anti-tumor effects of GFRAL-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed.</p> Results <p>GFRAL-Fc targets GDF15 to simultaneously prevent GDF15-CD48 interaction-driven ERK activation and block GDF15-GFRAL binding. Treatment with GFRAL-Fc achieved dual antitumor effects: reducing tumor progression and attenuating cancer-associated cachexia. Combination with PD-1 blockade further enhanced antitumor efficacy, resulting in a substantial decrease in tumor nodules. Mechanistic studies revealed that GFRAL-Fc reprograms the immunosuppressive tumor microenvironment by suppressing Treg activation while enhancing CD8<sup>+</sup> T cell cytotoxicity.</p> Conclusions <p>Our findings validate GDF15 targeting as a viable strategy to overcome checkpoint inhibitor resistance in HCC. The GFRAL-Fc fusion protein demonstrates multimodal therapeutic benefits through metabolic regulation and immune remodeling, providing a clinically translatable approach to optimize PD-1-based regimens. This study addresses critical gaps in current HCC management and warrants further clinical validation.</p> Graphical Abstract <p>Schematic diagram of GFRAL-Fc functional: After binding with GDF15, GFRAL-Fc inhibits the GDF15-GFRAL pathway to suppress cancer-associated cachexia, while also inhibiting the GDF15-CD48 pathway to reprograming the tumor immune microenvironment.</p> <p></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

GFRAL-Fc disarms GDF15 to reprogram tumor immunity and amplify PD-1 efficacy in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月15日

查看全文
  • Gege Shi,
  • Wangqian Zhang,
  • Fei Xie,
  • Jiaxin Shi,
  • Minghui Yan,
  • Lei He,
  • Zhaozhao Li,
  • Yang Xiao,
  • Duo Yu,
  • Haiyan Cao,
  • Haichen Du,
  • Yueyuan Qiu,
  • Kuo Zhang,
  • Shuning Wang,
  • Meng Li,
  • Jieyu Zhang,
  • Zhaowei Wang

摘要

Background

Checkpoint inhibitors have revolutionized hepatocellular carcinoma (HCC) treatment, yet their efficacy remains limited in advanced stages, with suboptimal objective response rates. Growth differentiation factor 15 (GDF15), a dual-functional cytokine implicated in tumor progression and immunosuppression, represents a promising therapeutic target. This study aims to develop a novel GDF15-targeted strategy to improve HCC management and synergize with PD-1 blockade.

Methods

GFRAL-Fc fusion proteins were generated by fusing the extracellular domain of GFRAL with IgG1 Fc. The anti-tumor efficacy and the anti-cachexia ability of GFRAL-Fc was evaluated in a spontaneous HCC model on GDF15 humanized mice. Additionally, the half-life and drug safety were evaluated in mice. To investigate the underlying mechanisms, a CyTOF analysis was utilized to analysis the immunoregulation effects of GFRAL-Fc within HCC. Finally, the anti-tumor effects of GFRAL-Fc in combination with Programmed Death-1 (PD-1) inhibitors were assessed.

Results

GFRAL-Fc targets GDF15 to simultaneously prevent GDF15-CD48 interaction-driven ERK activation and block GDF15-GFRAL binding. Treatment with GFRAL-Fc achieved dual antitumor effects: reducing tumor progression and attenuating cancer-associated cachexia. Combination with PD-1 blockade further enhanced antitumor efficacy, resulting in a substantial decrease in tumor nodules. Mechanistic studies revealed that GFRAL-Fc reprograms the immunosuppressive tumor microenvironment by suppressing Treg activation while enhancing CD8+ T cell cytotoxicity.

Conclusions

Our findings validate GDF15 targeting as a viable strategy to overcome checkpoint inhibitor resistance in HCC. The GFRAL-Fc fusion protein demonstrates multimodal therapeutic benefits through metabolic regulation and immune remodeling, providing a clinically translatable approach to optimize PD-1-based regimens. This study addresses critical gaps in current HCC management and warrants further clinical validation.

Graphical Abstract

Schematic diagram of GFRAL-Fc functional: After binding with GDF15, GFRAL-Fc inhibits the GDF15-GFRAL pathway to suppress cancer-associated cachexia, while also inhibiting the GDF15-CD48 pathway to reprograming the tumor immune microenvironment.