An Epigenetically Remodeled EMT–Inflammatory Clone Associated with Spatial Immune Exclusion in Clear Cell Renal Cell Carcinoma
- 1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China
Abstract
Clear cell renal cell carcinoma (ccRCC) exhibits intra-tumoral heterogeneity and spatial complexity that restrict immune infiltration, yet the malignant populations driving spatial immune exclusion remain elusive. We integrated scRNA-seq, paired scATAC-seq, spatial transcriptomics, and multiple bulk cohorts to identify the malignant subpopulation driving ccRCC progression. Multi-omics analyses, including malignancy inference, epigenomic profiling, cell–cell communication, and spatial modeling, characterized its molecular features and clinical relevance. We identified a malignant subpopulation co-activating epithelial–mesenchymal transition (EMT) and inflammatory programs, termed the aggressive EMT–inflammatory clone (AEIC). AEIC exhibited pronounced genomic instability, enhanced stemness, and poor prognosis across multicenter cohorts (p < 0.001). Chromatin accessibility revealed a MAZ/RUNX1-centered network driving key AEIC signature genes such as TGFBI and COL6A2. Cell–cell communication analysis suggested AEIC interacts with NK_CD16− cells via the COL6A2–(ITGA1+ITGB1) axis. Spatial analyses showed AEIC-enriched regions forming an extracellular matrix-rich barrier associated with NK_CD16− cell exclusion, M2-like macrophage polarization, and increased genomic instability. Finally, an AEIC-derived 16-gene signature stratified prognosis across independent cohorts and was associated with distinct drug-sensitivity patterns, including increased predicted sensitivity to Bortezomib and AZD4547. Overall, AEIC is associated with spatial and epigenetic remodeling in ccRCC, and the AEIC-derived signature supports prognostic stratification and further exploration of potential therapeutic vulnerabilities associated with the AEIC phenotype.
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BibTeX
@article{lan2026epigenetically,
title = {{An Epigenetically Remodeled EMT–Inflammatory Clone Associated with Spatial Immune Exclusion in Clear Cell Renal Cell Carcinoma}},
author = {Rifang Lan and Lixia Weng and Bingbing Cao and Aotuo Li and Jingyi Zhang and Hongbo Shi and Lei Yang and Yingli Lv},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219668},
url = {https://www.mdpi.com/1422-0067/27/21/9668},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - An Epigenetically Remodeled EMT–Inflammatory Clone Associated with Spatial Immune Exclusion in Clear Cell Renal Cell Carcinoma
AU - Rifang Lan
AU - Lixia Weng
AU - Bingbing Cao
AU - Aotuo Li
AU - Jingyi Zhang
AU - Hongbo Shi
AU - Lei Yang
AU - Yingli Lv
PY - 2026
DA - 2026/10/28
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219668
UR - https://www.mdpi.com/1422-0067/27/21/9668
AB - Clear cell renal cell carcinoma (ccRCC) exhibits intra-tumoral heterogeneity and spatial complexity that restrict immune infiltration, yet the malignant populations driving spatial immune exclusion remain elusive. We integrated scRNA-seq, paired scATAC-seq, spatial transcriptomics, and multiple bulk cohorts to identify the malignant subpopulation driving ccRCC progression. Multi-omics analyses, including malignancy inference, epigenomic profiling, cell–cell communication, and spatial modeling, characterized its molecular features and clinical relevance. We identified a malignant subpopulation co-activating epithelial–mesenchymal transition (EMT) and inflammatory programs, termed the aggressive EMT–inflammatory clone (AEIC). AEIC exhibited pronounced genomic instability, enhanced stemness, and poor prognosis across multicenter cohorts (p < 0.001). Chromatin accessibility revealed a MAZ/RUNX1-centered network driving key AEIC signature genes such as TGFBI and COL6A2. Cell–cell communication analysis suggested AEIC interacts with NK_CD16− cells via the COL6A2–(ITGA1+ITGB1) axis. Spatial analyses showed AEIC-enriched regions forming an extracellular matrix-rich barrier associated with NK_CD16− cell exclusion, M2-like macrophage polarization, and increased genomic instability. Finally, an AEIC-derived 16-gene signature stratified prognosis across independent cohorts and was associated with distinct drug-sensitivity patterns, including increased predicted sensitivity to Bortezomib and AZD4547. Overall, AEIC is associated with spatial and epigenetic remodeling in ccRCC, and the AEIC-derived signature supports prognostic stratification and further exploration of potential therapeutic vulnerabilities associated with the AEIC phenotype.
SN - 1422-0067
ER -