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