Research progress on the biological function and molecular mechanism of GDF-15 in solid malignant tumors

Growth differentiation factor 15 (GDF-15), a stress-responsive member of the transforming growth factor-β (TGF-β) superfamily, is consistently upregulated in multiple solid tumors and closely linked to poor clinical outcomes. This review offers a systematic overview of the pleiotropic functions and principal signaling pathways of GDF-15 in solid malignancies. Within the tumor microenvironment (TME), GDF-15 fuels tumor progression by promoting proliferation, sustaining stemness, remodeling metabolism, and conferring therapy resistance via the TGF-β, Leukemia Inhibitory Factor (LIF)-Signal Transducer and Activator of Transcription 3 (STAT3), and AKT pathways. Notably, GDF-15 orchestrates an immunosuppressive TME by limiting T cell infiltration and expanding regulatory T cells, thereby facilitating immune evasion and resistance to immune checkpoint inhibitors (ICIs). Systemically, GDF-15 contributes to cancer cachexia through activation of the brainstem glial-cell-line-derived neurotrophic factor family receptor α-like (GFRAL)-rearranged during transfection (RET) receptor axis. Accumulating preclinical evidence positions GDF-15 as a promising therapeutic target, particularly for mitigating cachexia and potentiating immunotherapy. However, the context-dependent and dualistic nature of GDF-15 signaling, varying with tumor type, microenvironment, and disease stage, poses substantial hurdles for clinical translation. Future efforts should focus on deciphering the molecular determinants underlying GDF-15's functional duality, paving the way for precise, context-tailored intervention strategies.