Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma
Year: 2026
Type: article
Abstract: Intratumor heterogeneity (ITH) undermines transcriptome-based stratification in intrahepatic cholangiocarcinoma (iCCA). Here, we integrate multi-omics data from multi-region, single-region, and single-cell RNA sequencing cohorts to systematically characterize gene expression ITH. We uncover that immune and stromal heterogeneity are primary drivers of ITH, leading to misclassification of a median 27.8% of tumors by existing subtyping systems. To overcome this, we identify a low-intratumor-heterogeneity/high-intertumor-variability (LIHV) gene set and develop an ITH-insensitive classification system defining five subgroups: inflammatory (SI), metabolic (SII), atypical (SIII-1), immune-silent (SIII-2), and neurodegenerative (SIII-3). These subgroups exhibit distinct clinical outcomes, molecular features, immune landscapes, and therapeutic vulnerabilities. GPRC5A and VTCN1 serve as robust immunohistochemical biomarkers for SI and SIII tumors, while serum CEA and CA19-9 identify inflammatory iCCA. Therapeutically, HSP90 inhibition synergizes with anti-PD1 in inflammatory iCCA, whereas combined anti-PD1 and anti-TIM3 suppresses neurodegenerative iCCA. Collectively, our study provides a robust molecular framework and actionable therapeutic strategies for iCCA.
Source: Cell Reports Medicine
Authors: Youpei Lin, Lihua Peng, Haichao Zhao, Penghui Lin, Lv Chen, Zunyun Gong, Jian Lin, Dongbing Liu, Xupeng Yang, Xiangze Song, Mao Zhang, Shuyi Ji, Junhua Rao, Huijuan Luo, Yifei Cheng, Xiaofang Chen, Guohe Song, Hao Hou, Dongning Rao, Tiancheng Zhang, Weiren Liu, Shu Zhang, Gaoyang Xu, Juan Zhang, Liyun Xiao, Yan Liang, Yang Liu, Yuhan Chen, Zhirou Cui, Xiaoying Wang, Jian Zhou, Qiang Gao, Kui Wu, Jia Fan
Institutions: Fudan University, Zhongshan Hospital, BGI Group (China), BGI Research, BGI Genomics, University of Chinese Academy of Sciences, First Affiliated Hospital Zhejiang University, Zhejiang University, Jinggangshan University, South China University of Technology, Tongji University, Shanghai East Hospital, Shanghai Medical College of Fudan University, State Key Laboratory of Genetic Engineering
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: National Natural Science Foundation of China, China Postdoctoral Science Foundation, Fudan University, Science and Technology Commission of Shanghai Municipality, National Science and Technology Major Project, National Postdoctoral Program for Innovative Talents, National Key Research and Development Program of China, National Key Research and Development Program of China Stem Cell and Translational Research
OpenAlex ID: W7143365875