The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors

Abstract

Tumor-infiltrated lymphocytes are exposed to many toxic metabolites and molecules in the tumor microenvironment (TME) that suppress their anti-tumor activity. Toxic metabolites, such as lactate and ketone bodies, are produced mainly by catabolic cancer-associated fibroblasts (CAFs) to feed anabolic cancer cells. These catabolic and anabolic cells make a metabolic compartment through which high-energy metabolites like lactate can be transferred via the monocarboxylate transporter channel 4. Moreover, a decrease in molecules, including caveolin-1, has been reported to cause deep metabolic changes in normal fibroblasts toward myofibroblast differentiation. In this context, metformin is a promising drug in cancer therapy due to its effect on oncogenic signal transduction pathways, leading to the inhibition of tumor proliferation and downregulation of key oncometabolites like lactate and succinate. The cross-feeding and metabolic coupling of CAFs and tumor cells are also affected by metformin. Therefore, the importance of metabolic reprogramming of stromal cells and also the pivotal effects of metformin on TME and oncometabolites signaling pathways have been reviewed in this study.

Current understanding of epigenetics role in melanoma treatment and resistance

“…HIF-1α is activated by post-translation modifications such as phosphorylation, acetylation, hydroxylation, and ubiquitination [ 32 , 37 ]. HIF-1α also has a prominent role in angiogenesis by affecting cellular metabolism, tumor invasion, vascular endothelial growth factor (VEGF), cell survival, and metastasis [ 32 , 33 , 38 – 40 ]. HIF-1α expression is related to aggressive characteristics of melanoma.…”

Glycolysis in tumor microenvironment as a target to improve cancer immunotherapy

“…In addition, the metabolic interaction between cells in the TME may play a crucial role in cancer behavior and immunity. For example, the enhanced methionine uptake promoted by SLC43A2 upregulation in cancer cells significantly causes T cell dysfunction ( Bian et al, 2020 ), the nutrient support of cancer-associated fibroblasts promotes cancer progression ( Mostafavi et al, 2022 ), and the metabolic symbiosis between glycolytic cancer cells and oxidative cancer cells ( Wang et al, 2021 ). These findings stress that metabolic cooperation and antagonism happening in TME is promising for novel target development.…”

“…For example, lactate and ketone bodies produced by cancer-associated fibroblasts (CAFs) produce can be utilized by cancer cells in the TME. Metformin disturbs the cross-feeding of CAFs and cancer cells to repress the additional nutrient support for cancers ( Mostafavi et al, 2022 ).…”

The role of macrophage subtypes and exosomes in immunomodulation

“…These reversible changes are essential during inflammation and its resolution phases [ 87 , 88 ]. Of note, the tumor microenvironment (TME) has a vital effect on cancer progression [ 89 , 90 ]. Macrophages are able to alter their features according to the TME.…”