Li Chunxiao, Xiong Liting, Yang Yuhan, Jiang Ping, Wang Junjie, Li Mengyuan, Wei Shuhua, Tian Suqing, Wang Yuexuan, Zhang Mi, Tang Jie
Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
Mol Cancer. 2025 Jan 28;24(1):34. doi: 10.1186/s12943-025-02238-5.
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.
索拉非尼是一种经美国食品药品监督管理局（FDA）批准用于晚期肝细胞癌（HCC）的药物，但面临耐药问题，部分原因是骨髓来源的抑制细胞（MDSCs）增强了肿瘤微环境（TME）中的免疫抑制作用。
在一系列体外和体内实验中使用了各种小鼠肝癌细胞系和MDSCs。这些实验包括皮下肿瘤模型、细胞活力测定、流式细胞术、免疫组织化学和RNA测序。对MDSCs进行趋化性、免疫抑制功能、脂肪酸氧化（FAO）和PPARα表达分析。评估了索拉非尼对肿瘤生长、MDSC浸润、分化和免疫抑制功能的影响，以及PPARα对这些过程的调节作用。
在此，我们发现索拉非尼治疗后TME中MDSCs的浸润增加且功能增强。此外，我们的结果表明索拉非尼诱导了由CCR2介导的MDSCs积累，并且CCR2的药理学阻断显著减少了MDSCs的迁移和肿瘤生长。机制上，索拉非尼促进了MDSCs的效应和脂肪酸摄取能力，并调节了过氧化物酶体增殖物激活受体α（PPARα）介导的脂肪酸氧化（FAO）。此外，在索拉非尼给药开始时喂食高脂饮食（HFD）的荷瘤小鼠的结局比喂食常规饮食的小鼠更差。PPARα的基因缺陷削弱了索拉非尼对肝癌小鼠中MDSCs的作用。PPARα的药理学抑制与索拉非尼具有协同抗肿瘤作用，而这种作用会因MDSCs的抑制而减弱。机制上，索拉非尼通过上调PPARα表达和抑制PU.1-CSF1R途径显著抑制巨噬细胞的分化。
总体而言，我们的研究表明索拉非尼通过促进PPARα介导的FAO增强了MDSCs的功能，并进一步增强了索拉非尼耐药性，这为饮食管理提供了思路，并改善了肝癌的治疗反应。
