Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application

Abstract

Background: N6-methyladenosine (m⁶A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m⁶A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.

Aim of review: The primary objective of this review is to comprehensively discuss the regulatory role of m⁶A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.

Key scientific concepts of review: This review aims to elaborate on the intricate networks governed by the m⁶A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m⁶A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Keywords: Cancer; Metabolites; Targeted therapy; Tumor immunosuppressive microenvironment; m(6)A.

Fig. 1

The function of m⁶A enzymes in cancer glycometabolism pathways. Notably, m⁶A enzyme-mediated regulation of tumor cell glycolysis primarily involves the Warburg effect, characterized by aerobic glycolysis.

Fig. 2

The functions of m⁶A enzymes involved in cancer amino acid metabolic pathways. Importantly, m⁶A enzyme-mediated alterations in amino acid metabolism within tumor cells are linked to the metabolic reprogramming of these cells.

Fig. 3

Implications of m⁶A enzymes in cancer lipid metabolic pathways. Notably, m⁶A enzyme-driven disruptions in lipid metabolism in tumor cells are associated with the metabolic reprogramming observed in these cells.

Fig. 4

Effects of m⁶A modification on immune and tumor cells within the TME. m⁶A modifications regulate the levels of intermediate metabolites within the TME, influencing the biological functions of immune and tumor cells.

Fig. 5

Dioxygenases catalyze net demethylation or hydroxylation reactions using α-KG and molecular oxygen as cosubstrates and producing succinate as a by-product. m⁶A modification promotes mitochondrial metabolism and produces succinate, fumarate, and 2-HG, whereas succinate,fumarate, and 2-HG have been shown to suppress FTO/ALKBH5 activity.