Yan Huishen, Lin Zhiwu, Zhang Jieying, Zhu Peiquan, Chen Yuquan, Liao Jingyuan
Department of Medical Science, Yangzhou Polytechnic College, Yangzhou, 225009, China.
Department of Thoracic Surgery, Ziyang Central Hospital, Ziyang, 641300, China.
Discov Oncol. 2025 Apr 1;16(1):443. doi: 10.1007/s12672-025-02074-5.
Esophageal cancer (EC) is a common malignant tumor, often diagnosed in its late stages due to the subtlety of early symptoms. Traditional chemotherapy inflicts significant harm on the organism; however, the emergence of targeted and immune therapies has conferred considerable survival advantages for patients with EC. However, the prolonged exposure of immune cells to the tumor microenvironment (TME) results in functional deterioration, thereby causing drug resistance and notably diminishing the therapeutic outcomes. Therefore, it is necessary to gain an in-depth understanding of the immune microenvironment of EC to find ways to overcome the development of resistance.
This study aimed to explore the causal relationships between cytokines, immune cell phenotypes, and the development of EC, with particular emphasis on their role in tumor progression and drug resistance. Using Mendelian randomization, we sought to identify key immune-related factors implicated in EC pathogenesis and evaluate their potential as therapeutic targets for overcoming resistance to treatment.
Through univariable MR, we found that two cytokines and twenty-two immune cell phenotypes are significantly associated with the incidence of EC. Further bidirectional MR analysis indicated interactions between two cytokines and five immune cells. Lastly, two-step MR analysis showed that there are mediating pathways in both directions between cytokines and immune cell phenotypes.
This research deepens the understanding of the mechanisms underlying the interactions between key cytokines and immune cells associated with the onset of EC. The research provides new insights into the issue of drug resistance within the esophageal cancer TME and offers novel perspectives for the development of targeted and immune-based therapies for EC.
食管癌（EC）是一种常见的恶性肿瘤，由于早期症状不明显，常被诊断为晚期。传统化疗对机体造成重大损害；然而，靶向治疗和免疫治疗的出现为食管癌患者带来了显著的生存优势。然而，免疫细胞长时间暴露于肿瘤微环境（TME）会导致功能恶化，从而产生耐药性并显著降低治疗效果。因此，有必要深入了解食管癌的免疫微环境，以找到克服耐药性发展的方法。
本研究旨在探讨细胞因子、免疫细胞表型与食管癌发生发展之间的因果关系，特别强调它们在肿瘤进展和耐药性中的作用。我们使用孟德尔随机化方法，试图确定与食管癌发病机制相关的关键免疫相关因素，并评估它们作为克服治疗耐药性的治疗靶点的潜力。
通过单变量孟德尔随机化分析，我们发现两种细胞因子和二十二种免疫细胞表型与食管癌的发病率显著相关。进一步的双向孟德尔随机化分析表明两种细胞因子与五种免疫细胞之间存在相互作用。最后，两步孟德尔随机化分析表明细胞因子与免疫细胞表型之间存在双向介导途径。
本研究加深了对与食管癌发病相关的关键细胞因子和免疫细胞之间相互作用机制的理解。该研究为食管癌TME中的耐药性问题提供了新的见解，并为食管癌靶向治疗和免疫治疗的发展提供了新的视角。
