Metabolic rewiring directs melanoma immunology

Abstract

Melanoma results from the malignant transformation of melanocytes and accounts for the most lethal type of skin cancers. In the pathogenesis of melanoma, disordered metabolism is a hallmark characteristic with multiple metabolic paradigms involved in, e.g., glycolysis, lipid metabolism, amino acid metabolism, oxidative phosphorylation, and autophagy. Under the driving forces of oncogenic mutations, melanoma metabolism is rewired to provide not only building bricks for macromolecule synthesis and sufficient energy for rapid proliferation and metastasis but also various metabolic intermediates for signal pathway transduction. Of note, metabolic alterations in tumor orchestrate tumor immunology by affecting the functions of surrounding immune cells, thereby interfering with their antitumor capacity, in addition to the direct influence on tumor cell intrinsic biological activities. In this review, we first introduced the epidemiology, clinical characteristics, and treatment proceedings of melanoma. Then, the components of the tumor microenvironment, especially different populations of immune cells and their roles in antitumor immunity, were reviewed. Sequentially, how metabolic rewiring contributes to tumor cell malignant behaviors in melanoma pathogenesis was discussed. Following this, the proceedings of metabolism- and metabolic intermediate-regulated tumor immunology were comprehensively dissertated. Finally, we summarized currently available drugs that can be employed to target metabolism to intervene tumor immunology and modulate immunotherapy.

Keywords: glycolysis; immunology; immunotherapy; melanoma; metabolism.

Figure 1

Reprogramming of autophagy in melanoma. During early stage, autophagy level in melanoma is significantly down-regulated, which is induced by MAPK activation-induced suppression of TFEB, the down-regulation of ATG5, and the down-regulation of SIRT6 and its-mediated IGF1R-AKT signaling. During advanced stage, autophagy level is prominent increased, which is related to the up-regulation of SIRT6 and its-mediated IGF1R-AKT signaling, and the up-regulation of lncRNA ZNNT1 and ATG12. Autophagy plays a bimodal role in melanoma progression, namely, acts as a tumor suppressor at early stage, whereas acts as a tumor promoter at advanced stage. .

Figure 2

The crosstalk between glycolysis and tumor immunology in melanoma. The dysregulation of glycolysis could exert regulatory multiple effects on the immunologic characteristic of tumor cells and the anti-tumor capacity of immune cells. On one hand, the activated glycolysis in melanoma cells lead to extracellular lactic acid accumulation, which can affect the function of macrophage, T cells and NK cells. On the other, glycolysis in T cells, NK cells and macrophages can also modulate their function and anti-tumor activity.

Figure 3

The role of metabolism in CAFs and its implication in melanoma progression. The deficient mitochondrial function induced by PGC1α deficiency triggers the activation of anaplerotic pathways to provide sufficient tricarboxylic acid cycle intermediates, so as to synthesize lipids and proteins to support tumor growth. In addition, CAFs display increased activity of L-arginase, which contributes to TIGIT and BTLA expression on CTLs and impairs the activity of CD8⁺T cells. What’s more, the knockout of ATF4 in fibroblasts leads to defects in collagen biosynthesis and deposition, so as to result in growth delay of melanoma. .

Figure 4

The role of tryptophan metabolism in melanoma immunology. On one hand, abnormally activated IDO1/TDO pathway of tryptophan in melanoma cells contributes to a diversified peptidome landscape and aberrant transframe peptides which could facilitate immune recognition. On the other, tryptophan in TME can affect the function and differentiation of T cells. .

Figure 5

The role of lipid metabolism in melanoma immunology. (A) Suppressive role of cholesterol in anti-tumor immunity. Cholesterol promotes the expression of exhaustion-related immune checkpoints in T cells and suppresses the cytotoxic function of Tc9 cells. (B) Facilitative role of cholesterol in anti-tumor immunity. Increase of cholesterol via targeting at ACAT1 causes enhanced T-cell receptor clustering as well as more efficient formation of the immunological synapse. In addition, increased cholesterol biogenesis via PPAR-γ could enhance the transcription of SREBF1 to optimize IFN-γ production. (C) During radiotherapy and immunotherapy, activated T cells can secret IFN-γ to suppress the expression of system Xc^- to induce lipid peroxidation and thereby ferroptosis.