Immunometabolism: A new target for improving cancer immunotherapy

Abstract

Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of "immunometabolism." Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes.

Keywords: Antitumor immunity; Cancer immunotherapy; Immune checkpoints; Immunometabolism; Tumor microenvironment.

Fig. 1

Overview of cell metabolism. The metabolism of glucose, fatty acids, and glutamine generates intermediates to support cell survival and proliferation. Glycolysis and FAO provide acetyl-CoA for oxidation through TCA cycle. The pentose phosphate pathway branching off glycolysis generates NADPH and ribose-5-phosphate for nucleotide synthesis. Cytosolic aspartate and acetyl-CoA generated by TCA cycle metabolites oxaloacetate and citrate are used for nucleotide and FAS, respectively. The intermediate malonyl CoA from the FAS pathway blocks CPT1, the rate-setting enzyme of FAO. CPT1, carnitine palmitoyltransferase I; ETC, electron transport chain; FAO, fatty acid oxidation; FAS, fatty acid synthesis; FASN, fatty acid synthase; FH, fumarate hydratase; GLUD, glutamate dehydrogenase; GLS, glutaminase; mIDH1/2, mutant isocitrate dehydrogenases 1 and 2; LDH, lactate dehydrogenase; SDH, succinate dehydrogenase; TCA, tricarboxylic acid.

Fig. 2

Metabolic evasion of the immune system by cancer. Cancer cells metabolically alter the tumor immune compartment through nutrient competition, release of immunosuppressive metabolites that can also facilitate the expansion and function of suppressive immune cells, such as M2 macrophages, myeloid-derived suppressor cells (MDSCs). Tumors impair effector function of T cells by limiting the nutrient availability in the tumor microenvironment (TME), e.g., glucose or amino acids deprivation. This can cause a mitochondrial function loss in T cells and poor tumor infiltration by T cells. Accumulation of lactate due to Warburg effects also inhibits glycolysis in T cells. Tumorinfiltrating dendritic cells (DCs) display a defect in antigen cross-presentation and T cell priming due to the presence of lactate, lipid accumulation, and enhanced FAO. Suppressive immune cells, including tumor-associated macrophages (TAMs) and MDSCs, can adapt to the metabolically challenged TME via their metabolic reliance on FAO, which lead to amplified immune suppression and tumor promotion. The hypoxia TME further enforces the activity of infiltrating myeloid cells in restricting the availability of amino acids that are essential for T cell activation. Targeting metabolic pathways in both tumor and immune cell can be therapeutically exploited to overcome immune suppression and reinvigorate immune functions for improved antitumor immunity.