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Abstract
Tumor cell phenotypes and anti-tumor immune responses are controlled by coordinated changes in metabolite abundance, but the cellular source of metabolite abundance and intratumoral metabolite heterogeneity and its phenotypic consequences remain poorly understood. To study the interaction between the immune microenvironment and the metabolic phenotypes, we used previously validated RNA signatures and compared their expression with metabolite abundances. This analysis revealed that the immune composition of the microenvironment drives intratumoral metabolite variation. Across cancer types, NAD+, a mediator of redox poise and a cofactor for numerous metabolic and non-metabolic reactions, is at lower abundance in immune cells compared to tumor cells. We also found the presence of rare cell populations, such as mast cells and activated dendritic cells, are associated with shifts in abundance of immunomodulatory molecules such as histamine and kynurenine. Investigating intratumoral heterogeneity using 187 multi-regionally sampled ccRCC tumors from 31 patients, we identified a common pattern of intratumoral heterogeneity that transcended all patients, characterized by correlated fluctuations in the abundance of metabolites (cysteine, glutathione, polyunsaturated fatty acids) and processes (OXPHOS and reactive oxygen species transcription) associated with ferroptosis. Local metabolic phenotypes therefore emerge in tandem with the immune microenvironment and influence ongoing tumor evolution. Our findings suggest that therapeutic strategies that rationally target the metabolome and immune microenvironment in combination may improve response to therapy, but care is needed to account for intratumoral heterogeneity of metabolic phenotypes.
