透明细胞肾细胞癌（ccRCC）的基因组图谱具有相当大的肿瘤内异质性，这是精准肿瘤学领域的重大障碍，并且在癌症的转移、复发和治疗耐药中发挥着关键作用。 ccRCC 肿瘤内异质性的机制尚未完全确定。我们从单细胞多组学角度整合了单细胞 RNA 测序 (scRNA-seq) 和转座酶可访问的染色质测序 (scATAC-seq) 数据。基于共识非负矩阵分解（cNMF）算法，功能异质性癌细胞被分为代谢、炎症和EMT元程序，空间转录组测序（stRNA-seq）提供癌细胞不同元程序的空间信息。大量RNA测序（RNA-seq）数据揭示了三个元程序的功能异质性癌细胞的高临床预后价值，转录因子调控网络和基序活性揭示了调节功能异质性ccRCC细胞的关键转录因子。研究了微环境中不同元程序和其他细胞亚群之间的相互作用。最后，我们评估了不同元程序的癌细胞对不同抗癌药物的敏感性。我们的研究结果揭示了 ccRCC 的肿瘤内异质性及其调控网络，并为促进合理治疗策略的设计提供了新的视角。

The genomic landscape of clear cell renal cell carcinoma (ccRCC) has a considerable intra-tumor heterogeneity, which is a significant obstacle in the field of precision oncology and plays a pivotal role in metastasis, recurrence, and therapeutic resistance of cancer. The mechanisms of intra-tumor heterogeneity in ccRCC have yet to be fully established. We integrated single-cell RNA sequencing (scRNA-seq) and transposase-accessible chromatin sequencing (scATAC-seq) data from a single-cell multi-omics perspective. Based on consensus non-negative matrix factorization (cNMF) algorithm, functionally heterogeneous cancer cells were classified into metabolism, inflammatory, and EMT meta programs, with spatial transcriptomics sequencing (stRNA-seq) providing spatial information of such disparate meta programs of cancer cells. The bulk RNA sequencing (RNA-seq) data revealed high clinical prognostic values of functionally heterogeneous cancer cells of three meta programs, with transcription factor regulatory network and motif activities revealing the key transcription factors that regulate functionally heterogeneous ccRCC cells. The interactions between varying meta programs and other cell subpopulations in the microenvironment were investigated. Finally, we assessed the sensitivity of cancer cells of disparate meta programs to different anti-cancer agents. Our findings inform on the intra-tumor heterogeneity of ccRCC and its regulatory networks and offers new perspectives to facilitate the designs of rational therapeutic strategies.