Blockade of the GDF15/GFRAL Axis: Translational Advances in Cachexia, Immune Suppression, and Beyond

INTRODUCTION: Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the transforming growth factor β (TGF-β) superfamily. In normal physiology, GDF15 is expressed in multiple tissues at low concentrations. However, its expression significantly increases following many pathological conditions, such as tissue injury, inflammation, mitochondrial dysfunction, and cancer. GDF15 has emerged as a significant biomarker and a promising therapeutic target since the identification of its central nervous system-restricted receptor, Glial cell line-derived neurotrophic factor family receptor α-like (GFRAL)-REarranged during Transfection proto-oncogene (RET). METHODS: We conducted a narrative review of the published literature on the molecular mechanisms of GDF15, with special focus on interventional studies using anti-GDF15 drugs. This review highlights the therapeutic potential of blockade of the GDF15/GFRAL axis based on current preclinical and clinical data. RESULTS: GDF15 is a multifaceted factor that exerts a central role in regulating energy balance, demonstrating context-dependent effects. It acts as a key mediator of anorexia and weight loss in cancer cachexia. Furthermore, GDF15 contributes to the remodeling of the tumor immune microenvironment by inhibiting immune cell functions. Therapeutic strategies developed based on this, such as GDF15 antagonists, neutralizing antibodies, GFRAL receptor fusion proteins, as well as the combined application of GDF15-targeted drugs and immune checkpoint inhibitors, have yielded promising results in clinical trials. We also include a discussion of the potential limitations in the development of anti-GDF15 drugs. DISCUSSION: GDF15-targeted drugs have shown potential benefits in reversing cancer cachexia and may enhance anti-tumor immunity, but this remains to be confirmed in larger, controlled studies. The primary challenge in targeting GDF15 lies in the complexity and context-dependent nature of its biological functions. CONCLUSION: GDF15 represents a highly compelling therapeutic target for metabolic and oncological diseases. Overcoming the challenges posed by its biological complexity is essential to successfully translating GDF15-targeted strategies into precision medicine applications.