Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy

Abstract

Metabolic programming in the tumor microenvironment (TME) alters tumor immunity and immunotherapeutic response in tumor-bearing mice and patients with cancer. Here, we review immune-related functions of core metabolic pathways, key metabolites, and crucial nutrient transporters in the TME, discuss their metabolic, signaling, and epigenetic impact on tumor immunity and immunotherapy, and explore how these insights can be applied to the development of more effective modalities to potentiate the function of T cells and sensitize tumor cell receptivity to immune attack, thereby overcoming therapeutic resistance.

Keywords: T cell; checkpoint; immunotherapy; metabolism; metabolite; tumor microenvironment.

Figure 1.. Interaction of oncogenic, immune, and metabolic pathways in cancer.

Mutations in key oncogenes (such as KRAS, TP53, and BRCA2) drive tumor initiation. Immunosuppressive networks, including regulatory T cells and inhibitory myeloid cells, inhibit tumor immunity, enabling cancer establishment and progression. Metabolic reprogramming in the tumor microenvironment fuels tumor proliferation and enables tumor immune evasion. Thus, cancer is a genetic, immune, and metabolic disorder. Targeting the interaction of oncogenic, immune, and metabolic pathways in cancer is considered a logical approach towards a new generation of cancer therapy.

Figure 2.. Crosstalk between cancer cells and effector T cells in the tumor microenvironment.

The fate of tumor cells is determined by crosstalk between cancer cells and effector T cells in the TME. T cells induce tumor cell apoptosis via perforin and granzyme B and promote tumor cell ferroptosis via IFNγ and specific fatty acids in the TME. Counterintuitively, chronic immune stress, including T cell derived IFNγ, rewires tumor cell metabolism - enabling tumor stemness, progression, and resistance to ICB. Tumor cells impair T cell survival and effector function via nutrient deprivation and immune regulatory oncometabolites.

Figure 3.. Oncometabolite production in the tumor microenvironment.

Glucose is imported into the cell and metabolized to pyruvate and lactate via glycolysis. Intermediate metabolites, such as itaconate, succinate, and 2-hydroxyglutarate (2HG) are generated during glycolysis. These metabolites can function beyond their metabolic role and mediate immune regulation in the TME. Loss-of-function mutations in genes that encode the TCA cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH) lead to accumulation of the oncometabolites fumarate and succinate, respectively. Gain-of-function of isocitrate dehydrogenase 1 (IDH1) or IDH2 leads to accumulation of D-2-hydroxyglutarate (D-2-HG). Loss-of-function of the enzymes D-2-hydroxyglutarate dehydrogenase (D2HGDH) and L-2-hydroxyglutarate dehydrogenase (L2HGDH), which catalyze the oxidation of D-2-HG and L-2-HG to α-ketoglutarate, results in the accumulation of D-2-HG and L-2-HG, respectively.