Abstract 5382: Comprehensive characterization of renal cell carcinomas identifies metabolic reprogramming of the tumor microenvironment associated with disease progression

Abstract Background: Renal cell carcinoma (RCC) is one of the most frequent urological cancers with the most common histological subtype being clear cell renal cell carcinoma (ccRCC), an immunologically and histologically diverse tumor which is associated with a poor clinical outcome as up to 40% of ccRCC patients develop metastases. While significant progress has been made in the development of immunotherapy for ccRCC, there are still many unanswered questions about the mechanisms of immune evasion and resistance, and the development of predictive biomarkers for optimal treatment strategies for individual patients. Recently, it has become clear that cellular metabolism may play a significant role in the immune response to ccRCC tumors, affecting both the ability of T-cells to function and the overall composition of the tumor microenvironment (TME). This remodeled TME leads to changes in nutrients and metabolites that can promote an immunosuppressive environment and prevent lymphocyte activation and recruitment, eventually promoting T-cell exhaustion. Methods: We performed transcriptomic and spatial profiling of 16 ccRCC patient samples across all clinical TNM stages (Stages I-IV) to define the changes in metabolic processes and infiltrating immune cells with advancing disease. Specifically, we included the spatial MultiOmyx™ IF multiplexing assay (NeoGenomics Laboratories, Inc.) using the new MO2.0 workflow with enhanced whole slide capability coupled to the NanoString nCounter® Metabolic Pathways Panel to investigate metabolic reprogramming, cellular stress, and the relationship to the composition of the TME in advancing disease progression in ccRCC. Results and Conclusions: We identified significant changes associated with the TME, especially immunosuppressive immune cells in advanced disease, coupled to the identification of several metabolism-related genes that correlated with immune infiltrates in ccRCC. Identifying and understanding these metabolic alterations within the different staging of RCC will help in designing new targeted therapies and improving diagnostic tools to better care for patients with this disease. Citation Format: Kirsteen H. Maclean, Lakshmi Chandramohan, Qingyan Au, Harry Nunns, Jiong Fei, Erinn Parnell, Anna Juncker-Jensen. Comprehensive characterization of renal cell carcinomas identifies metabolic reprogramming of the tumor microenvironment associated with disease progression [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 5382.