Inhibition of GDF15/GFRAL: A novel opportunity for the treatment of solid tumors

Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, exerts multifaceted and context-dependent roles in cancer biology. This review integrates current evidence on the dual nature of GDF15, emphasizing its functional transition from a tumor-suppressive mediator during early carcinogenesis to a potent driver of tumor progression in advanced disease. We highlight its capacity to reshape the immunosuppressive tumor microenvironment through multiple mechanisms: suppression of cytotoxic T cell and natural killer (NK) cell infiltration, promotion of regulatory T cell (Treg) differentiation, and impairment of dendritic cell maturation and function. Additionally, we delineate the central role of the GDF15/GFRAL-RET signaling axis in mediating cancer cachexia via hypothalamic regulation of appetite and systemic induction of muscle atrophy and adipose tissue loss. Accumulating data position GDF15 as a critical node linking cellular senescence, mitochondrial stress, and resistance to anticancer therapies. Finally, we discuss emerging therapeutic approaches-such as GDF15-neutralizing antibodies, GFRAL antagonists, and selective RET inhibitors-that are designed to concurrently suppress tumor growth and mitigate cachexia, offering a promising integrated strategy for the management of advanced solid tumors.