Tumor Microenvironment-Derived Metabolites: A Guide to Find New Metabolic Therapeutic Targets and Biomarkers

SIMPLE SUMMARY: Cancer cells reprogram their metabolism to meet the bioenergetic, biosynthetic and redox demands required to maintain tumor formation, growth and dissemination. Additionally, rewired metabolism in the tumor microenvironment contributes to immune evasion by depleting key nutrients required for mounting a proper immune response, but also by producing immunosuppressive metabolites. Altered cancer metabolism can be exploited therapeutically by targeting cancer cell activities required for biomass and energy production, but also by alleviating the immunosuppressive properties of the tumor microenvironment. Using imaging techniques (i.e., magnetic resonance spectroscopy (MRS), positron emission tomography (PET), magnetic resonance imaging (MRI)) or the liquid chromatography coupled to mass spectrometry (LC-MS)-based analysis of biofluids, altered metabolites produced by dysregulated cancer metabolism can be used as noninvasive biomarkers for diagnosis and therapy. ABSTRACT: Metabolic reprogramming is a hallmark of cancer that enables cancer cells to grow, proliferate and survive. This metabolic rewiring is intrinsically regulated by mutations in oncogenes and tumor suppressors, but also extrinsically by tumor microenvironment factors (nutrient and oxygen availability, cell-to-cell interactions, cytokines, hormones, etc.). Intriguingly, only a few cancers are driven by mutations in metabolic genes, which lead metabolites with oncogenic properties (i.e., oncometabolites) to accumulate. In the last decade, there has been rekindled interest in understanding how dysregulated metabolism and its crosstalk with various cell types in the tumor microenvironment not only sustains biosynthesis and energy production for cancer cells, but also contributes to immune escape. An assessment of dysregulated intratumor metabolism has long since been exploited for cancer diagnosis, monitoring and therapy, as exemplified by 18F-2-deoxyglucose positron emission tomography imaging. However, the efficient delivery of precision medicine demands less invasive, cheaper and faster technologies to precisely predict and monitor therapy response. The metabolomic analysis of tumor and/or microenvironment-derived metabolites in readily accessible biological samples is likely to play an important role in this sense. Here, we review altered cancer metabolism and its crosstalk with the tumor microenvironment to focus on energy and biomass sources, oncometabolites and the production of immunosuppressive metabolites. We provide an overview of current pharmacological approaches targeting such dysregulated metabolic landscapes and noninvasive approaches to characterize cancer metabolism for diagnosis, therapy and efficacy assessment.