Abstract 5247: Comprehensive characterization of pseudocapsules in clear cell renal cell carcinoma reveals unique invasion mechanisms: A multi-omics investigation

Abstract Clear cell renal cell carcinoma (ccRCC) represents the most common subtype of renal cell carcinoma, accounting for approximately 70% of cases. Notably, the majority of ccRCC tumors are surrounded by a prominent pseudocapsule tissue, highlighting its potential diagnostic, prognostic, and therapeutic relevance. To comprehensively understand the implications of pseudocapsules in ccRCC, we constructed an extensive multi-omics atlas. The cohort included single-cell RNA sequencing, spatial transcriptomics, proteomics, and extracellular matrix (ECM) proteomics, derived from 36 ccRCC cases. These analyses were further augmented with functional assays and animal studies, enabling a multi-dimensional exploration of pseudocapsule biology. Our cohort analysis demonstrated that pseudocapsules are predominantly composed of fibroblasts and a rich diversity of immune cells, a finding corroborated through immunofluorescence (IF) and immunohistochemistry (IHC). The tissue was also characterized by a substantial accumulation of extracellular matrix components. Importantly, pseudocapsule invasion revealed significant alterations in the tumor microenvironment (TME). During tumor invasion, CD8+ T cells and dendritic cells (DCs) within the pseudocapsule exhibited increased activation, accompanied by pronounced exhaustion. Concurrently, tumor-associated fibroblasts underwent functional reprogramming, transitioning from a myofibroblast-like state (myoCAF) to an inflammatory CAF phenotype (iCAF). These iCAFs primarily interacted with T cells and promoted their exhaustion, which was critical to ccRCC progression. Additionally, our investigation identified a loss of chromosome 14q during tumor cell invasion. Notably, the FOS gene on chromosome 14 was significantly downregulated and identified as a key gene. Clinical data from large patient cohorts revealed that low FOS expression was associated with advanced tumor stage, higher histological grade, and poorer overall survival. Functional assays demonstrated that FOS overexpression reduced the invasive potential of ccRCC cell lines in vitro, whereas FOS knockdown enhanced lung metastasis in vivo. Transcriptomic analysis further indicated that FOS is involved in regulating extracellular matrix dynamics and immune-related pathways. These findings provide novel insights into the role of pseudocapsules in ccRCC and highlight critical molecular mechanisms underlying tumor progression. By uncovering key invasion biomarkers and therapeutic targets, this study lays the groundwork for precision medicine approaches in ccRCC management. Citation Format: Xiyi Wei, Yitong Pan, Weiyu Kong, Da Zhong, Zijie Yu, Yang Wang, Longjun Ma, Zhou Yang, Yize Li, Chenxi Tian, Bing Yao, Ninghong Song, Chao Qin. Comprehensive characterization of pseudocapsules in clear cell renal cell carcinoma reveals unique invasion mechanisms: A multi-omics investigation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5247.