Niu Jingze, Wu Wenda, Zhang Huayue, Li Zelin, Meng Xiaojie, Xu Baocai
School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230601, China.
Engineering Research Center of Bio-Process, Ministry of Education, Hefei University of Technology, Hefei, 230601, China.
Dig Dis Sci. 2025 Aug 11. doi: 10.1007/s10620-025-09230-5.
The development of liver cancer in China is mainly caused by HBV, HCV infection, and exposure to aflatoxin. Especially in warm and humid southern regions, aflatoxin pollution poses a threat to health, emphasizing the urgency of research on related liver cancer.
Firstly, through in vivo experiments, the important role of AFB1 in mediating changes in the immune microenvironment of liver cancer has been preliminarily validated. In addition, statistical and mIHC analysis were conducted on clinical specimens collected from patients exposed and non-exposed to aflatoxin. Transcriptome sequencing technology enabled us to further explore the specific molecular mechanisms underlying the occurrence of HCC caused by AFB1 exposure. Finally, the synergistic effect of targeting IL-6 on PD1 therapy was validated through an in vivo animal tumor model.
We found that AFB1 indirectly influences M2-like macrophage polarization by upregulating IL-6 expression in tumor cells through the NF-κB signaling pathway. To address this challenge, we evaluated the efficacy of targeting IL-6 in combination with PD1 antibody therapy in a subcutaneous tumor model. Our results demonstrate that the combination treatment significantly reduces tumor growth, decreases the number of M2-like macrophages, and enhances CD8 + T cell infiltration compared to monotherapy with PD1 antibody alone.
Overall, our study highlights the potential of targeting IL-6 as a therapeutic strategy and suggests avenues for further research and clinical studies to validate and translate these findings into clinical applications, ultimately leading to improved outcomes for patients with AFB1-associated hepatocellular carcinoma.
中国肝癌的发生主要由乙肝病毒（HBV）、丙肝病毒（HCV）感染以及黄曲霉毒素暴露引起。尤其是在温暖潮湿的南方地区，黄曲霉毒素污染对健康构成威胁，凸显了对相关肝癌研究的紧迫性。
首先，通过体内实验初步验证了黄曲霉毒素B1（AFB1）在介导肝癌免疫微环境变化中的重要作用。此外，对从暴露和未暴露于黄曲霉毒素的患者收集的临床标本进行了统计分析和多重免疫组化（mIHC）分析。转录组测序技术使我们能够进一步探索AFB1暴露导致肝癌发生的具体分子机制。最后，通过体内动物肿瘤模型验证了靶向白细胞介素-6（IL-6）对程序性死亡蛋白1（PD1）治疗的协同作用。
我们发现AFB1通过核因子κB（NF-κB）信号通路上调肿瘤细胞中IL-6的表达，间接影响M2样巨噬细胞极化。为应对这一挑战，我们在皮下肿瘤模型中评估了靶向IL-6联合PD1抗体治疗的疗效。我们的结果表明，与单独使用PD1抗体单药治疗相比，联合治疗显著降低肿瘤生长，减少M2样巨噬细胞数量，并增强CD8 + T细胞浸润。
总体而言，我们的研究突出了靶向IL-6作为一种治疗策略的潜力，并为进一步的研究和临床研究提供了途径，以验证这些发现并将其转化为临床应用，最终改善AFB1相关肝细胞癌患者的预后。
