Blocking the CXCL1-CXCR2 axis enhances the effects of doxorubicin in HCC by remodeling the tumor microenvironment via the NF-κB/IL-1𝛽/CXCL1 signaling pathway

Abstract Inflammation is a core mechanism for oncogenesis. Chemokines act as important inflammation mediators in chronic inflammation and the tumor inflammatory response. However, limited information is known about chemokines in hepatocellular carcinoma (HCC), a disease that is almost entirely derived from chronic liver inflammation. Here, we explored the protumor effects of CXCL1, a commonly elevated inflammatory chemokine in cirrhosis, in HCC. This protumor feature was confirmed in clinical samples of human HCC. CXCL1 enhances tumorigenesis in the hepatic inflammatory microenvironment directly through tumor cells and indirectly through recruitment of macrophages. Increasing the number of macrophages in the tumor microenvironment (TME) promoted tumor cell Epithelial-mesenchymal transition (EMT) capacity and significantly elevated CXCL1 levels in the TME partly through NF-κB/IL-1𝛽 activation. To investigate the potential therapeutic value of CXCL1 in HCC with inflammatory background, blocking CXCL1 and blocking CXCL1 combined with the chemotherapy agent doxorubicin (DOX), which aimes to reshape the TME, were administered. It has been shown that blocking CXCL1-CXCR2 inhibits tumor progression and reduces macrophage recruitment in the TME. The combination regimen has been shown to have a synchronous effect in HCC by reducing pro-tumor macrophages in the TME and suppressing tumor cell progression. This provides insight into therapeutic strategies for treating HCC patients with high CXCL1 expression.