DNA methylation mediates the immunosuppressive tumour microenvironment in metastatic endometrial clear cell carcinoma

作者：Huiqing Jia, Yang Chen, Guofeng Ma, Shiwen Xu, Xiangyan Zhang, Lianpeng Chang, Ping Yang, Yujing Xiao, Xuefeng Xia, Shukun Zhang, Huaxiao Tang, Yilin Mou, Lina Zhang, Haoyan Wang, Jing Bai, Xin Yi, Xiaoming Xing · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105954 · 被引用次数：2 · 研究领域：Endometrial and Cervical Cancer Treatments、Epigenetics and DNA Methylation、Immune cells in cancer

BACKGROUND: Endometrial clear cell carcinoma (ECCC) is a rare and highly aggressive histological subtype of endometrial cancer with marked metastatic potential. The molecular characteristics and underlying mechanisms governing its metastatic behaviour remain poorly understood. This study aimed to delineate molecular distinctions between metastatic (Pm) and non-metastatic (Pn) primary ECCC tumours, elucidate DNA methylation-mediated regulatory mechanisms driving metastasis, and identify potential epigenetic biomarkers and therapeutic targets. METHODS: This multicentre study involved 51 individuals diagnosed with ECCC, leading to the establishment of two independent cohorts: a sequencing cohort (n = 35) for integrated whole-genome methylation and transcriptomic analysis, and a tissue microarray (TMA) cohort (n = 16) to validate key findings. FINDINGS: Tumours exhibiting metastasis were found to possess a profoundly immunosuppressive tumour microenvironment (TME), evidenced by reduced density of tumour-infiltrating lymphocytes (TILs), especially within subsets of anti-tumour immune cells. Further analysis highlighted differential hypermethylation events in Pm tumours that acted as crucial epigenetic switches regulating immune responses. Specifically, methylation at ETS1-binding sites influenced ETS1 regulon activity, thus broadly regulating immune response processes. Epigenetic silencing of key genes in the T cell receptor (TCR) signalling pathway, such as LCK, CD3E, and ZAP70, ...