Cancer immunometabolism: advent, challenges, and perspective

Abstract

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

Keywords: Cancer-immunity cycle; Cancer-immunometabolism subcycle; Immunity; Immunometabolism; Metabolic adaptation; Metabolic reprogramming.

Fig. 1

Metabolic competition between tumor cells and immune cells. The availability of nutrients for metabolic processes is fundamental for cell survival, along with tumor cells and immune cells are no exception. Competitive uptake of nutrients by tumor cells in the tumor microenvironment may occur at all stages of immune cell life. Metabolite paucity tilts the energy balance in favour of the tumor cells (the negative direction), which in turn leads to further dysfunction of immune cells (such as naïve T cells, B cells, natural killer cells, macrophages, neutrophils, and dendritic cells, etc.)

Fig. 2

Immune-related intracellular energy metabolism and substance synthesis. The diagram shows the metabolic activities and synthetic reactions that occur in the cell under enzymatic reactions and correlate with or might cause immune changes (enzymes are labeled in purple, nutrients or metabolites are labeled in green, molecules or targets are labeled in yellow, and inhibitors are labeled in grey). For example, lipid uptake from the TME leads to elevated intracellular cholesterol concentrations, which in turn triggers ER stress (inducing CD8⁺ T cell dysfunction). The PI3K/AKT pathway, which is activated by growth factor signals, stimulates the mTOR family molecules, which in turn elicits vital activities such as protein synthesis, cell proliferation, and autophagy, and so on. The mTOR family molecules are also regulated by amino acids. FA synthesis is coordinated sequentially by several enzymes involving ACC1 (inhibition of ACC1 reduces TH17 cell differentiation but enhances the formation of memory CD4+ T cells). And C75 inhibits FASN which in turn diminishes FA synthesis. In addition, the induction of FA oxidation was associated with an increase in AMPK activity (AMPK also promotes the generation of memory CD8⁺ T cells). JHU083 inhibited glutaminase-mediated glutaminolysis. TME, tumor microenvironment; SREBP, sterol regulatory element binding protein; ER, endoplasmic reticulum; PI3K, phosphatidylinositol 3-kinase; FA, Fatty acid; ACC1, acetyl-CoA carboxylase 1; PDH, pyruvate dehydrogenase; αKG, α-ketoglutarate; FASN, fatty acid synthase; AMPK, AMP-activated protein kinase

Fig. 3

Double-edged swords in cancer immunometabolism. Implications of FA synthesis (1) and catabolism (2) on tumor progression. 1) Upregulation of SREBP activity in T_reg cells synergizes with FASN to promote FA synthesis, which in turn activates the PI3K pathway and facilitates the maturation of T_reg cells. Specific deletion of SCAP (an essential factor for SREBP activity) by T_reg cells enhances anti-PD-1 immunotherapy; 2) Leptin downregulates CD8⁺ T cell effector function through activation of STAT3-FAO and inhibition of glycolysis. Ablating T cell STAT3 or treatment with perhexiline (FTO inhibitor) in obese mice spontaneously developing breast tumor reduces FAO, increases glycolysis and CD8⁺ T effector cell functions, leading to inhibition of breast tumor development. Additionally, the effects of lactate on cancer and immune cells in TME can be complex and difficult to decipher, which is further confounded by acid protons (byproducts of glycolysis). 3) Tumor-derived lactate is an inhibitor of CD8⁺ T cell cytotoxicity. Cytotoxic T cells shunt succinate out of the TCA circulation to promote autocrine signalling via the succinate receptor (SUCNR1). Moreover, cytotoxic T cells rely on PC to replenish succinate. Lactate decreases PC activity, and similarly, inhibition of PDH restores PC activity, succinate secretion, and SUCNR1 activation; 4) Lactate increases CD8⁺ T cell stemness and enhances anti-tumor immunity. Subcutaneous injection of lactate in mice transplanted with MC38 tumors leads to CD8⁺ T cell-dependent tumor growth inhibition. Mechanistically, lactate inhibits histone deacetylase activity, leading to increased acetylation of the Tcf7 super-enhancer site, H3K27, which results in increased Tcf7 gene expression. FA, fatty acid; SREBP, sterol regulatory element binding protein; FASN, fatty acid synthase; PI3K, phosphatidylinositol 3-kinase; FAO, fatty acid oxidation; TME, tumor microenvironment; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase

Fig. 4

Disruptor of the virtuous cycle: the cancer-immunometabolism subcycle. In fact, antigen release occurs consistently in most patients with malignant tumors. Nevertheless, the CI cycle of Chen et al. suggests that it does not imply that the inevitable occurrence of cancer cell death events (the left cycle). Metabolic-related factors may be responsible for the disruption of the CI cycle. Considering the cancer-immunometabolism subcycle (the right cycle) proposed in this review, it is reasonable to assume that metabolism-related factors may contribute to the interruption of the CI cycle (the left cycle). When immune cells reach the tumor microenvironment through the vascular endothelium or basement membrane, nutrient deprivation as well as accumulation of local toxic substances accelerate the formation of tumor immunosuppressive microenvironment. Thereby, the infiltrating immune cells become dysfunctional, such as altered macrophage polarization, diminished killing effect of T cells and NK cells, and formation of NETs, and so on. As the result, the CI cycle is impaired and failed to stimulate a potent and sustainable immune response. CI cycle, cancer-immunity cycle; NK cells, natural killer cells; NETs, neutrophil extracellular traps