Cell reports. Medicine · 2026
Robust transcriptomic hallmarks targeting intratumor heterogeneity in intrahepatic cholangiocarcinoma.
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Lin Youpei, Peng Lihua, Zhao Haichao, Lin Penghui, Chen Lv, Gong Zunyun, Lin Jian, Liu Dongbing, Yang Xupeng, Song Xiangze, Zhang Mao, Ji Shuyi, Rao Junhua, Luo Huijuan, Cheng Yifei, Chen Xiaofang, Song Guohe, Hou Hao, Rao Dongning, Zhang Tiancheng, Liu Weiren, Zhang Shu, Xu Gaoyang, Zhang Juan, Xiao Liyun, Liang Yan, Liu Yang, Chen Yuhan, Cui Zhirou, Wang Xiaoying, Zhou Jian, Gao Qiang, Wu Kui, Fan Jia
Аннотация
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.