image: GDF15 functions as a dual-edged regulator within the TME. On one hand, it suppresses anti-tumor immunity by impairing T cell recruitment and adhesion through inhibition of LFA-1/β2-integrin–mediated interactions with activated endothelial cells, blocking dendritic cell and granulocyte infiltration, and promoting the immunosuppressive activity of M2 macrophages. These effects collectively establish a “cold” TME that facilitates tumor immune evasion. On the other hand, GDF15 exhibits context-dependent tumor-protective effects where its expression limited local tumor growth in a CD8⁺ T cell–dependent manner, although it simultaneously promoted distant metastasis. Beyond immune regulation, GDF15 also remodels the stromal compartment: it stimulates cancer-associated fibroblasts (CAFs) to adopt a myofibroblast phenotype and enhance collagen secretion, thereby increasing tumor stiffness and invasiveness. Moreover, fibroblasts are an important source of GDF15 that further reinforces tumor progression. In the bone microenvironment, GDF15 enhances osteoblast activity, promotes CCL2 and RANKL secretion, recruits osteoclasts, and activates osteoclastogenesis, ultimately facilitating prostate cancer bone metastasis. Together, these findings underscore the complex and sometimes paradoxical functions of GDF15 in prostate cancer progression, immune regulation, chemoresistance, and metastasis. EC: Endothelial cell; LFA-1: Lymphocyte function-associated antigen-1; CCL2: C-C Motif Chemokine Ligand 2; RANKL: Receptor activator of nuclear factor kappa-B ligand; RANK: Receptor activator of nuclear factor kappa-B. Solid lines represent the direct effects of GDF15, while dashed lines indicate that the corresponding cell types can secrete GDF15 to form feedback.
Credit: Chinese Medical Journal
Prostate cancer (PCa) remains a significant global health challenge, with rising morbidity rates and poor prognosis associated with advanced stages, particularly in cases complicated by cachexia—a severe wasting syndrome that drastically reduces patient survival and quality of life. The complexity of PCa progression necessitates the identification of new, targeted solutions beyond conventional treatments.
The newly published review focuses intensely on Growth Differentiation Factor 15 (GDF15), a distinct member of the Transforming Growth Factor-beta (TGF-β) superfamily. While GDF15’s role in other cancers is varied, the review clarifies its significant, multifaceted involvement in PCa. Mechanistically, GDF15 is hypothesized to drive PCa progression and promote cachexia through its interactions with PCa lipid metabolism and stromal activation.
Furthermore, GDF15 plays a critical role in mediating PCa bone metastasis. For instance, it enhances the function of stromal cells (primarily osteoblasts), increasing the secretion of CCL2 and RANKL, which subsequently recruits osteoclasts and activates osteoclastogenesis, ultimately facilitating the growth of metastatic PCa within the bone microenvironment.
A major challenge in advanced PCa treatment is the development of chemoresistance, particularly to standard agents like docetaxel. The review emphasizes GDF15’s impact in this area, suggesting it is a crucial player in drug responses. Studies have indicated that GDF15 acts as a cytoprotective mechanism in prostate carcinomas exposed to chemotherapy, directly contributing to resistance. Data from androgen-independent PCa cell lines show that GDF15 is upregulated in docetaxel-resistant cells, and its knockout restored docetaxel sensitivity in resistant cells. This highlights GDF15 as a promising target to resensitize tumors to existing chemotherapy agents, supporting the finding that GDF15 inhibition might be a potential therapeutic strategy for improving docetaxel efficacy.
The clinical utility of GDF15 extends to diagnosis, surveillance, and prognosis. While Prostate-Specific Antigen (PSA) is the current primary indicator, its lack of tumor specificity frequently leads to false positives. GDF15 offers a more nuanced approach. Serum GDF15 levels are lower in localized PCa but significantly higher in metastatic PCa compared to normal tissue.
Crucially, the review notes the synergistic power of combining GDF15 with established markers. An algorithm combining GDF15 and PSA, termed the MIC-PSA score, specifically enhances PCa diagnosis and can reduce unnecessary biopsies by 27% compared to using PSA alone. Furthermore, combining GDF15 with a panel of other markers has demonstrated superior performance in predicting aggressive low-risk PCa. Beyond serum, GDF15's potential as an independent predictor of poorer cancer-specific survival, and its ability to distinguish indolent from lethal localized PCa, establishes it as a valuable prognostic tool.
Perhaps the most exciting finding is the advancement of monoclonal antibodies targeting GDF15 in clinical trials. These antibodies aim to disrupt the GDF15-mediated signaling pathways that drive cachexia and chemoresistance. Key monoclonal antibodies in clinical development include: AV-380, an inhibitory antibody which has shown efficacy in reversing cachexia-related phenotypes, rehabilitating weight, muscle, and fat mass in preclinical models; NGM120, a novel GFRAL antagonist which targets the receptor for GDF15 and has demonstrated anti-cancer activity in advanced PCa patients in a Phase 1a trial, with one patient achieving a partial response; and Visugromab, which neutralizes GDF15 to improve the effectiveness of PD1/PDL1 immunotherapy by enhancing immune cell infiltration into the tumor microenvironment. Other promising candidates include Ponsegromab and AZD8853, which are also undergoing clinical evaluation for treating cancer-related cachexia and potentially overcoming immunotherapy resistance.
The review concludes that the complex interactions involving GDF15 offer numerous points for therapeutic intervention, marking GDF15 as an indispensable target in developing next-generation precision medicine approaches for prostate cancer patients.
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Reference
DOI: https://doi.org/10.1097/CM9.0000000000003876
About Yang Lu from West China Hospital, Sichuan University
Dr. Lu Yang is a Professor and Deputy Director of the Department of Urology at West China Hospital, Sichuan University. He holds a Ph.D. in Urology from Sichuan University and completed postdoctoral training in Molecular Pharmacology/Urology at UCLA. His research focuses on urological cancers, particularly prostate cancer, and the development of targeted therapies. Dr. Yang has published over 150 peer-reviewed articles in high-impact journals such as Signal Transduction and Targeted Therapy and Molecular Cancer. He has received multiple prestigious awards, including the Prostate Cancer Foundation’s Young Investigator Award.
Funding information
This study was supported by the grants from the National Natural Science Foundation of China (Nos. 82170785, 81974099, 81974098, 82170784), National Key Research and Development Program of China (No. 2021YFC2009303), the program from Science and Technology Department of Sichuan Province (No. 2021YFH0172), Young Investigator Award of Sichuan University 2017 (No. 2017SCU04A17), Technology Innovation Research and Development Project of Chengdu Science and Technology Bureau (No. 2019-YF05-00296-SN), Sichuan University—Panzhihua Science and Technology Cooperation Special Fund (No. 2020CDPZH-4)
Journal
Chinese Medical Journal
Article Title
Decoding GDF15: Impact on prostate cancer metabolism, chemoresistance, and clinical applications
Article Publication Date
24-Nov-2025