Emodin Decreases Tumor-Associated Macrophages Accumulation and Suppresses Bladder Cancer Development by Inhibiting CXCL1 Secretion from Cancer-Associated Fibroblasts

Tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) are the most abundant stromal cells in the bladder cancer (BC) microenvironment (TME). However, the detailed mechanisms underlying TAM-CAF communication and their contributions to BC progression remain incompletely understood. Emerging evidence shows that Emodin exerts anti-tumor effect on several tumor models by targeting TME. To date, the impact of Emodin on BC has not been previously reported. Our study firstly demonstrated that Emodin significantly inhibited tumor growth and reduced TAM accumulation in a murine BC model. Emodin markedly decreased serum levels of multiple chemokines in tumor-bearing mice, with CXCL1 showing the most pronounced reduction. Strikingly, Emodin selectively suppressed CXCL1 secretion in CAFs but not in TAMs or tumor cells. Furthermore, the decrease in TAM migration induced by Emodin was dependent on CAF-derived CXCL1. Using a subcutaneous tumor model, we found that Emodin failed to inhibit tumor growth when CXCL1-deficient CAFs were co-injected with tumor cells, underscoring the critical role of CXCL1 in this process. Bioinformatics analysis further revealed that elevated CXCL1 levels correlated negatively with invasive/metastatic potential and overall survival in BC patients. In conclusion, our findings establish that Emodin delays BC progression by disrupting CXCL1-mediated crosstalk between CAFs and TAMs.