海军医科大学陈磊团队宣布他们揭示了胆囊癌的多组学分析确定了与疾病进展相关的不同肿瘤微环境。2025年6月26日，国际知名学术期刊《自然—遗传学》发表了这一成果。

该课题组研究人员创建了来自102名患者的1117245个细胞的单细胞图谱和突变景观，揭示了细胞结构、空间相互作用和分子功能的时空特征，并概括了五个局部生态系统分层临床结果。综合上皮程序AI-EPI结合空间转录组分析，揭示了高度恶性肿瘤亚型（GM16）和AREG⁺ T细胞,B 原发性腺癌前转移生态位内的细胞、树突状细胞和巨噬细胞亚型。

体外和体内实验表明，除了促进转移外，AREG还通过EGFR-pERK-EGR1信号通路促进肿瘤细胞中CXCL5的表达，导致中性粒细胞浸润增加，阻碍免疫治疗的有效性。他们的研究提供了GBC微环境的时空景观，并揭示了预防免疫治疗耐药性的潜在策略。

据介绍，胆囊癌（GBC）是最具侵袭性的胆道肿瘤，死亡率高。由于局部肿瘤微环境中驱动其进展的原位驱动因素的性质，GBC的治疗面临治疗挑战。

附：英文原文

Title: Multi-omic analysis of gallbladder cancer identifies distinct tumor microenvironments associated with disease progression

Author: Zhou, Tao, Wu, Yanhong, Li, Shuai, Qiu, Xinyao, Liu, Erdong, Xie, Zhihua, Shi, Xuebing, Zhang, Yani, Ma, Guosheng, Guo, Wenbo, Wang, Xiang, Wang, Kaiting, Yao, Xiaomeng, Hu, Ji, Shen, Siyun, Yang, Shuai, Jiang, Xiaoqing, Fu, Jing, Wang, Hongyang, Gu, Jin, Chen, Lei

Issue&Volume: 2025-06-26

Abstract: Gallbladder carcinoma (GBC) is the most aggressive biliary tract cancer and is associated with a high mortality rate. Treatment of GBC faces therapeutic challenges owing to the elusive nature of in situ drivers within the local tumor microenvironment that drive its progression. Here, we created a single-cell atlas of 1,117,245 cells and a mutational landscape from 102 patients, which unveiled spatial–temporal characterizations of cellular constitutions, spatial interplays and molecular functions, and generalized five local ecosystems stratifying clinical outcomes. An integrated epithelial program, AI-EPI, combined with spatial transcriptome analysis, revealed the concurrent localization of a highly malignant tumor subtype (GM16) and AREG+ Tcell, Bcell, dendritic cell and macrophage subtypes within the pro-metastatic niche of primary adenocarcinomas. In vitro and in vivo experiments suggest that in addition to promoting metastasis, AREG facilitates CXCL5 expression in tumor cells through EGFR–pERK–EGR1 signaling, leading to increased neutrophil infiltration and impeding the effectiveness of immunotherapy. Our study provides a spatial–temporal landscape of the GBC microenvironment and sheds light on potential strategies for preventing immunotherapy resistance.

DOI: 10.1038/s41588-025-02236-9

Source: https://www.nature.com/articles/s41588-025-02236-9