Figure 3.
In hepatocellular carcinoma, CAF-derived CCL5 promotes metastasis by binding to specific receptors, CCR5, and stabilizing HIF-1α under normoxia, upregulating one of the EMT genes ZEB1 and promoting TB development. In CRC, CCL5 blockade reduces tumor growth, decreases migration of tumor cells, reduces metastases, and decreases infiltration of Tregs in the tumor. CCL5 can stabilize PD-L1 in vitro and in vivo. CCR5 can also modulate TGF-β activity, which subsequently promotes an EMT. TB cells secrete high levels of CCL5, which recruits fibroblasts through CCR5–SLC25A24 signaling and leads to the development of a characteristic fibroblast cluster around TB cells at the invasive front of CRC. This further facilitates tumor angiogenesis and collagen synthesis, recruitment of CAFs, and promotes malignant progression. CCR5 can also modulate TGF-β activity, which subsequently promotes an EMT and increases tumor cell migration via the activation of the NF-κB pathway.