Targeting the GDF15-GFRAL Pathway in NSCLC Cachexia: From Stress Responses to Targeted Therapies

Cancer cachexia is a devastating, multifactorial wasting syndrome that significantly contributes to cancer-related mortality and drastically reduces patient quality of life. While numerous inflammatory cytokines drive this pathology, clinical trials targeting most of these factors have historically yielded limited success. Recently, growth differentiation factor 15 (GDF15) and its hindbrain-restricted receptor, glial cell-derived neurotrophic factor (GDNF) family receptor alphalike (GFRAL), have emerged as critical mediators of cachexia, driving tissue wasting through both appetite suppression and active metabolic reprogramming. This review synthesizes the molecular biology, structural characteristics, and stress-induced regulatory mechanisms of the GDF15- GFRAL axis. We highlight paradigm-shifting preclinical findings—including our discovery that tumor-derived GDF15 dictates wasting in STK11/LKB1-mutant non-small cell lung cancer (NSCLC) cachexia. Furthermore, we evaluate the promising landscape of GDF15-GFRAL targeted therapeutics currently advancing through clinical trials. Finally, we propose that identifying early genetic biomarkers, such as STK11/LKB1 mutations, is crucial for deploying these targeted interventions during the prodromal stages of cachexia, ultimately expanding the therapeutic window and improving patient survival.