The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment

Abstract

Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies.

GLS1 mediates SREBP-1 to promote lipid metabolism in hepatocellular carcinoma through PI3K/AKT/mTORC1 signaling pathway

“…Metabolic abnormalities fuel carcinogenesis and tumor adaption to the local microenvironment, which in turn aid cancer cell survival [18,19] . This process is referred to as "metabolic reprogramming", which is a series of adaptations clonally chosen during carcinogenesis by creating metabolites with varied functionalities at various levels [20,21] .…”

Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy

“…Unlike normal cells, cancers need to maintain malignant proliferation by altering their metabolic patterns. , Glutamine metabolism, a crucial metabolic pathway in tumor cells, is closely associated with maintaining redox homeostasis. , Glutaminase (GLS) is a key enzyme in glutamine metabolism that catalyzes the production of glutamate from glutamine, where glutamate is an essential raw material for the de novo synthesis of GSH. − Tumor cells synthesize more GSH by up-regulating the activity of GLS involved in glutamine metabolism to eliminate excessive ROS for maintaining intracellular redox homeostasis. , Blocking glutamine metabolism by GLS inhibitors is an ideal solution to prevent PDT-generated ROS from being annihilated by overexpressed GSH in order to address the problem of insufficient tumor immunogenicity elicited by PDT alone. In addition, glutamine metabolism is also closely related to the formation of the ITM. − As a major component in the ITM, immunosuppressive M2-type TAMs are more dependent on glutamine metabolism than M1-type TAMs. , Achieving glutamine deprivation by inhibiting glutamine metabolism can enhance the phenotype and function of M1 macrophages and simultaneously decrease the phenotype and function of M2 macrophages. − This is an method to reverse the ITM, which can further enhance the immunotherapeutic effect of PDT.…”

“…Unlike normal cells, cancers need to maintain malignant proliferation by altering their metabolic patterns. 15,16 Glutamine metabolism, a crucial metabolic pathway in tumor cells, is closely associated with maintaining redox homeostasis. 17,18 Glutaminase (GLS) is a key enzyme in glutamine metabolism that catalyzes the production of glutamate from glutamine, where glutamate is an essential raw material for the de novo synthesis of GSH.…”