7 / 2026-01-23 10:31:27

Single-cell multi-omics and spatial transcriptomics of clear cell renal cell carcinoma reveal chromatin priming and cellular plasticity: insights into tumor origin and immune heterogeneity

Single-cell multi-omics ，,spatial transcriptomics,clear cell renal cell carcinoma,chromatin priming,cellular plasticity

Clear cell renal cell carcinoma (ccRCC) is a highly heterogeneous urological malignancy that poses major clinical challenges. To dissect its regulatory programs and spatial–transcriptional complexity, we integrated single-nucleus multiome profiling (snATAC-seq + snRNA-seq) with spatial transcriptomics on tumor and matched paratumor tissues. This approach delineated cellular composition, spatial organization, chromatin accessibility, and transcriptional regulatory networks at single-cell resolution. Focusing on key compartments, we identified progenitor-like proximal tubule (PT) subpopulations in paratumor kidneys, predominantly regulated by AP-1 transcription factors and enriched in oncogenic pathways, supporting their role as a reservoir for malignant transformation. In tumor-infiltrating CD8⁺ T cells, stage-specific transcriptional programs underlying exhaustion were revealed. Leveraging joint chromatin accessibility and gene expression profiling from the same nuclei, pseudotime analysis demonstrated synchronous activation of lineage-determining genes in PT cells (e.g., CUBN, LRP2), but early accessibility of terminal exhaustion-associated genes in T cells preceding transcription (e.g., LAG3, HAVCR2, TOX2). This temporal decoupling highlights fate poising as a mechanism of stage-specific plasticity and suggests opportunities for epigenetic reprogramming. In the tumor microenvironment, we identified a distinct TAM-CTSL macrophage subset enriched in pro-angiogenic and pro-invasive programs, spatially localized to tumor–stromal interfaces, regulated by AP-1 under hypoxia, and associated with metastasis across cohorts. Collectively, our study provides an integrative atlas of ccRCC, illuminating dynamic changes in progenitor-like PT cells as putative cells of origin, uncovering chromatin priming as a shared mechanism of lineage commitment and immune dysfunction, and defining macrophage programs linked to progression. These insights expand the mechanistic understanding of ccRCC and inform therapeutic strategies targeting tumor origin and the immune microenvironment.