The interplays between GDF15 and cells in TME. GDF15: Growth differentiation factor 15; PCa: Prostate cancer; TME: Tumor microenvironment (IMAGE)
Caption
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
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