The effects of metabolism on the immune microenvironment in colorectal cancer

Abstract

Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.

Fig. 1. The three metabolisms on the TME of CRC.

The three major metabolisms of CRC, their specific metabolic pathways and downstream products have effects on the various immune components of TME and consequently influence the progression of CRC. TME tumor microenvironment, CRC colorectal cancer.

Fig. 2. Effects of amino acid metabolic reprogramming on CRC.

1) Glutamine was upregulated in CRC by reducing the effect of acetate as a carbon source for the TCA cycle and ultimately downregulating CD8 + T cells. 2) Tryptophan is metabolized in two ways to Kyn and IDO. On one hand, Kyn affects CD8 + T cells, M2 TAMs, Tregs and ultimately promotes CRC progression via TOX, AHR and FOXP3 respectively. Reduction of IDO is also able to reduce the TH17/TH1 response through AHR, which in turn promotes the development of CRC. Kyn kynurenine; IDO indoleamine 2,3-dioxygenase 1; TAMs tumour-associated macrophages; Tregs T regulatory cells; TOX thymocyte selection-associated HMG box protein; AHR aryl hydrocarbon receptor; FOXP3 forkhead box protein.

Fig. 3. Effects of glucose metabolic reprogramming on CRC.

1) The rise in three proxies marked the upregulation of glycolysis in CRC and hyperglycaemia in CRC, both of which resulted in worsening colorectal cancer by affecting T cells through the rising G6PD, MondoA-TXNIP signalling pathway, and Akt/mTORC1-CRC cellular autophagy pathway, respectively. 2) Lactate metabolism is upregulated in CRC, and upregulation of LDHA downregulates CD8 + T cells through downregulation of TH1-INFγ, and also enables polarization of TAMs to M2 TAMs through G protein-coupled receptor-dependent expression of ICER. G6PD glucose-6-phosphate dehydrogenase; LDHA lactate dehydrogenase A Gene; ICER inducible cAMP early repressor.

Fig. 4. Effects of lipid metabolic reprogramming on CRC.

1) In fatty acid metabolism, LDs and PGE2 are upregulated through ATGL/HSL-FAA, PGE2/EP4 and PGE2/EP1-Fas/FasL to upregulate M2 TAMs and downregulate CD8 + T cells. And upregulation of CPT1A, a key enzyme in fatty acid metabolism, also downregulates T cells and Teffs in two different ways. In sum, the end result of fatty acid metabolism contributes to the immune escape of CRC. 2) Upregulation of cholesterol itself activates the ROS- NLRP3-CCL5-p65/STAT3- CSN5-PD-L1 pathway to directly promote cancer cell growth, and in another way downregulates CD8 + T cells through the rise of PD-L1 and marker 2B4. This is followed by a rise in its product DCA, which in turn downregulates CD8 + T cells, p53 and converts regulatory T cells to proinflammatory one through upregulation of beta-linked proteins in three ways, all of which ultimately promote CRC development. 3) Phospholipids upregulate CD8 + T cells via agpat4/LPA/p38/p65-IL1β/IL-6 upregulation; on the other hand, phospholipids also upregulate M1 macrophage-dependent T-cells via camptothesomes. ultimately phospholipids act as heterodimers in metabolic reprogramming to inhibit CRC. LDs lipid drops; PGE2 prostaglandin E2; CPT1A carnitine palmitoyltransferase 1 A; ATGL adipose triglyceride lipase; HSL hormone-sensitive lipase; DCA deoxycholic acid; LPA lysophosphatidicacid.