Sorafenib enhanced the function of myeloid-derived suppressor cells in hepatocellular carcinoma by facilitating PPARα-mediated fatty acid oxidation

Abstract

Sorafenib, an FDA-approved drug for advanced hepatocellular carcinoma (HCC), faces resistance issues, partly due to myeloid-derived suppressor cells (MDSCs) that enhance immunosuppression in the tumor microenvironment (TME). Various murine HCC cell lines and MDSCs were used in a series of in vitro and in vivo experiments. These included subcutaneous tumor models, cell viability assays, flow cytometry, immunohistochemistry, and RNA sequencing. MDSCs were analyzed for chemotaxis, immunosuppressive functions, fatty acid oxidation (FAO), and PPARα expression. The impact of sorafenib on tumor growth, MDSC infiltration, differentiation, and immunosuppressive function was assessed, alongside the modulation of these processes by PPARα. Here, we revealed increased infiltration and enhanced function of MDSCs in TME after treatment with sorafenib. Moreover, our results indicated that sorafenib induced the accumulation of MDSCs mediated by CCR2, and pharmacological blockade of CCR2 markedly reduced MDSCs migration and tumor growth. Mechanistically, sorafenib promoted the effect and fatty acid uptake ability of MDSCs and modulated peroxisome proliferator-activated receptor α (PPARα)-mediated fatty acid oxidation (FAO). In addition, tumor-bearing mice fed a high-fat diet (HFD) at the beginning of sorafenib administration had worse outcomes than mice fed a regular diet. Genetic deficiency of PPARα weakens the effect of sorafenib on MDSCs in mice with HCC. Pharmacological inhibition of PPARα has a synergistic anti-tumor effect with sorafenib, which is attenuated by the inhibition of MDSCs. Mechanistically, sorafenib significantly inhibited the differentiation of macrophages by upregulating PPARα expression and suppressing the PU.1-CSF1R pathway. Overall, our study demonstrated that sorafenib enhanced the function of MDSCs by facilitating PPARα-mediated FAO and further augmenting sorafenib resistance, which sheds light on dietary management and improves the therapeutic response in HCC.