Immunometabolic coevolution defines unique microenvironmental niches in ccRCC

Tumor cell phenotypes and anti-tumor immune responses are shaped by local metabolite availability, but intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remain poorly understood. To study IMH, we profiled tumor/normal regions from clear cell renal cell carcinoma (ccRCC) patients. A common pattern of IMH transcended all patients, characterized by correlated fluctuations in the abundance of metabolites and processes associated with ferroptosis. Analysis of intratumoral metabolite-RNA covariation revealed that the immune composition of the microenvironment, especially the abundance of myeloid cells, drove intratumoral metabolite variation. Motivated by the strength of RNA-metabolite covariation and the clin-ical significance of RNA biomarkers in ccRCC, we inferred metabolomic profiles from the RNA sequencing data of ccRCC patients enrolled in 7 clinical trials, and we ultimately identifyied metabolite biomarkers associated with response to anti-angiogenic agents. Local metabolic phenotypes, therefore, emerge in tandem with the immune microenvironment, influence ongoing tumor evolution, and are associated with therapeutic sensitivity.

Automated summary

The availability of local metabolites shapes tumor cell phenotypes and anti-tumor immune responses, but the understanding of intratumoral metabolite heterogeneity (IMH) and its phenotypic consequences remains limited. Through analyzing clear cell renal cell carcinoma (ccRCC) patients, a common pattern of IMH was identified, characterized by fluctuations in metabolites associated with ferroptosis. The variations in intratumoral metabolites were driven by the immune composition of the microenvironment, particularly the abundance of myeloid cells. By inferring metabolomic profiles from RNA sequencing data, metabolite biomarkers associated with response to anti-angiogenic agents in ccRCC patients were identified.