Yao Jiaxi, Xu Tong, Wang Chenyuan, Xie Junfeng, Jiang Qing
Department of Urology, The Second Hospital of Chongqing Medical University, No1. Yixueyuan Rd, Yuzhong District, Chongqing, China.
Department of Urology, The First Hospital of China Medical University, Shenyang, 110001, China.
Clin Exp Med. 2025 Aug 13;25(1):291. doi: 10.1007/s10238-025-01807-8.
Metabolic reprogramming is a key feature of clear cell renal cell carcinoma (ccRCC), and metabolic abnormality can lead to significant changes in gene expression, resulting in the immunosuppressive microenvironment. In this study, we used a combination of single-cell RNA sequencing and bulk RNA sequencing to investigate the relationships between ccRCC metabolic reprogramming and immune exhaustion. Metabolic subtypes of ccRCC patients were constructed using bulk RNA sequencing. Tumor cells of different metabolic subtypes were analyzed and extracted by the Scissor algorithm, using single-cell RNA sequencing. The molecular mechanisms of abnormal metabolic regulating tumor immunity were explored using cell-cell communication analysis. In addition, the correlations between relevant molecules and immune exhaustion signals were verified in ccRCC by immunohistochemistry. The molecular mechanisms of metabolic abnormalities leading to immune exhaustion were validated via Western blotting, ELISA, cell co-culture and immunotherapy models. ccRCC patients can be divided into MT1 and MT2 metabolic subtypes. The MT2 subtype has a poorer prognosis and lower response to immunotherapy. Abnormal metabolism of arachidonic acid is a prominent feature of the MT2 subtype, and activates the MDK signaling pathway. As a secreted protein, MDK can further recruit immunosuppressive cells, such as Treg, Tex, and TAM. Blocking the arachidonic acid COX metabolic pathway significantly reduces the expression and secretion levels of MDK, thereby reprogramming the tumor microenvironment to promote anti-tumor immunity. Abnormal metabolism of arachidonic acid plays an important role in promoting immune exhaustion by activating the MDK signaling pathway. MDK may serve as an important biomarker for predicting the immune therapy response in ccRCC. By reducing MDK secretion, targeting blockade of arachidonic acid metabolism may be an effective treatment strategy to enhance the efficacy of immunotherapy in ccRCC.
代谢重编程是肾透明细胞癌（ccRCC）的一个关键特征，代谢异常可导致基因表达的显著变化，从而产生免疫抑制微环境。在本研究中，我们结合单细胞RNA测序和批量RNA测序来研究ccRCC代谢重编程与免疫耗竭之间的关系。使用批量RNA测序构建ccRCC患者的代谢亚型。利用单细胞RNA测序，通过Scissor算法分析并提取不同代谢亚型的肿瘤细胞。使用细胞间通讯分析探索代谢异常调节肿瘤免疫的分子机制。此外，通过免疫组织化学在ccRCC中验证相关分子与免疫耗竭信号之间的相关性。通过蛋白质免疫印迹法、酶联免疫吸附测定、细胞共培养和免疫治疗模型验证代谢异常导致免疫耗竭的分子机制。ccRCC患者可分为MT1和MT2代谢亚型。MT2亚型预后较差，对免疫治疗的反应较低。花生四烯酸的代谢异常是MT2亚型的一个突出特征，并激活MDK信号通路。作为一种分泌蛋白，MDK可进一步招募免疫抑制细胞，如调节性T细胞（Treg）、耗竭性T细胞（Tex）和肿瘤相关巨噬细胞（TAM）。阻断花生四烯酸COX代谢途径可显著降低MDK的表达和分泌水平，从而重新编程肿瘤微环境以促进抗肿瘤免疫。花生四烯酸的代谢异常通过激活MDK信号通路在促进免疫耗竭中起重要作用。MDK可能是预测ccRCC免疫治疗反应的重要生物标志物。通过减少MDK分泌，靶向阻断花生四烯酸代谢可能是提高ccRCC免疫治疗疗效的有效治疗策略。
