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Related Experiment Video

Updated: Jul 8, 2026

Assessment of Human Natural Killer Cell Events Driven by FcγRIIIa Engagement in the Presence of Therapeutic Antibodies
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De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.

Haitao Wang1,2, Tianzhen Hua2,3, Meiling Wang2

  • 1Senior Department of Hematology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 7, 2026
PubMed
Summary

De novo designed minibinders effectively neutralize Growth Differentiation Factor 15 (GDF15), reversing cancer cachexia and restoring immunotherapy efficacy.

Keywords:
GDF15RFdiffusioncancer cachexiade novo protein designimmune checkpoint blockade

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Area of Science:

  • Biochemistry
  • Protein Engineering
  • Cancer Biology

Background:

  • Cancer-associated cachexia is a severe condition causing weight loss and reduced survival.
  • Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia, but effective neutralization strategies are limited.

Purpose of the Study:

  • To design novel protein-based therapeutics targeting the GDF15-GFRAL interaction.
  • To develop mechanism-defined strategies for combating cancer cachexia and enhancing cancer therapy.

Main Methods:

  • Structure-guided de novo protein design using computational tools (RFdiffusion, ProteinMPNN, AlphaFold 3).
  • Experimental validation of minibinder affinity, stability, and GDF15 neutralization.
  • In vivo testing in multiple tumor models to assess cachexia reversal and immunotherapy response.

Main Results:

  • High-affinity GDF15 minibinders with picomolar binding and structural stability were designed.
  • Minibinders effectively suppressed GDF15-GFRAL signaling and reversed cachexia in vivo, improving body weight and survival.
  • GDF15 neutralization restored sensitivity to anti-PD-1 immunotherapy, enhancing anti-tumor effects through CD8+ T cell activation.

Conclusions:

  • De novo designed minibinders provide a potent and mechanistically defined approach to neutralize the GDF15-GFRAL axis.
  • These minibinders offer a promising therapeutic strategy for cancer cachexia and can synergize with immunotherapy.