Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma PMID: 41916296

ADC Targets in Oncology

2026-04-10

Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma

Cell Rep Med. 2026 Apr 21;7(4):102708. doi: 10.1016/j.xcrm.2026.102708.

Youpei Lin ¹ , Lihua Peng ² , Haichao Zhao ¹ , Penghui Lin ³ , Lv Chen ¹ , Zunyun Gong ⁴ , Jian Lin ⁵ , Dongbing Liu ⁶ , Xupeng Yang ¹ , Xiangze Song ⁷ , Mao Zhang ¹ , Shuyi Ji ⁸ , Junhua Rao ⁹ , Huijuan Luo ³ , Yifei Cheng ¹ , Xiaofang Chen ¹⁰ , Guohe Song ¹ , Hao Hou ¹⁰ , Dongning Rao ¹ , Tiancheng Zhang ¹ , Weiren Liu ¹ , Shu Zhang ¹ , Gaoyang Xu ¹⁰ , Juan Zhang ¹ , Liyun Xiao ² , Yan Liang ³ , Yang Liu ¹⁰ , Yuhan Chen ¹⁰ , Zhirou Cui ¹⁰ , Xiaoying Wang ¹ , Jian Zhou ¹ , Qiang Gao ¹¹ , Kui Wu ¹² , Jia Fan ¹³

Affiliations

1. Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University, Shanghai 200032, China.
2. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China.
3. BGI Genomics, Shenzhen 518083, China.
4. College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100000, China.
5. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
6. BGI Genomics, Shenzhen 518083, China; Jiangxi Provincial Key Laboratory of Organ Development and Epigenetics, School of Basic Medicine, Jinggangshan University, Ji'an 343009, China.
7. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
8. Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200123, China.
9. BGI, Shenzhen 518083, China.
10. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100000, China.
11. Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China. Electronic address: [email protected].
12. State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Hangzhou 310030, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100000, China; Jiangxi Provincial Key Laboratory of Organ Development and Epigenetics, School of Basic Medicine, Jinggangshan University, Ji'an 343009, China. Electronic address: [email protected].
13. Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Zhongshan Hospital, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200433, China. Electronic address: [email protected].

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.

Keywords

GPRC5A; HSP90 inhibitor; cholangiocarcinoma; immunotherapy; intratumor heterogeneity; molecular classification; multi-omics; precision oncology; tumor biomarker; tumor immune microenvironment.