Intergrated Multi-omics Sequencing Reveals Metabolic Reprograms in the Progression of ccRCC

ccRCC is a complex disease with remarkable immune and metabolic heterogeneity. Here, we present a TJ-RCC cohort, performing genomic, transcriptomic, proteomic, metabonomic and spatial multi-omic profiling on 100 ccRCC cases. Using the scRNA-seq-derived signature, we identify 4 subtypes. Multilevel profiling distinguishes a unique ccRCC subtype, De-clear cell differentiated (DCCD) -ccRCC, with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, extremely inhibited metabolic activity, enhanced nutrients uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD indicates worse outcomes and higher recurrence rate, indicating it cannot be cured by nephrectomy alone. This study provides a treatment strategy based on immune subtypes, which could enable precise clinical management of ccRCC.肾透明细胞癌（clear cell Renal Cell Carcinoma, ccRCC）是一种具有显著免疫与代谢异质性的复杂疾病。本研究建立TJ-RCC队列，对100例ccRCC病例开展基因组、转录组、蛋白质组、代谢组及空间多组学分析。基于单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）衍生的特征签名，本研究鉴定出4种ccRCC亚型。通过多维度组学分析，本研究区分出一种独特的ccRCC亚型——去透明细胞分化型肾透明细胞癌（DCCD-ccRCC），该亚型具备独特的代谢特征。DCCD癌细胞以脂滴更少、代谢活性显著受抑、营养摄取能力增强及增殖速率较高为典型特征，可导致不良预后。通过单细胞与空间轨迹分析，本研究证实DCCD是ccRCC进展的常见模式。即便在I期患者中，DCCD亚型仍提示更差的临床结局与更高的复发率，表明仅通过肾切除术无法治愈该亚型。本研究提出基于免疫亚型的治疗策略，可为ccRCC的精准临床管理提供有力支撑。