Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Abstract

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

Keywords: cancer cell metabolism; immunotherapy; metabolic reprogramming; targeted therapy; tumour microenvironment.

Figure 1

Overview of cancer cell metabolic reprogramming. Cancer cells require extensive metabolic reprogramming to fuel anabolic growth via increased nucleotide biosynthesis, protein synthesis, and FA synthesis. There is elevated glycolysis even under aerobic conditions (Warburg effect), which allows for the production of intermediates to be channelled into the PPP for nucleotide biosynthesis. However, a majority of tumours still retain oxidative capacity to produce ATP via OXPHOS. Glutaminolysis is also upregulated in many tumours for the production of α-KG to fuel the TCA cycle. Increased glutaminolysis also produces glutathione (GSH) to defend against oxidative stress. Central to these metabolic changes is the PI3K/Akt/mTOR pathway. Downstream effectors that are activated by mTORC signalling include the transcription factors HIF-1 and SREBP.

Figure 2

Key players of the metabolic crosstalk in the TME. Key players involved in the extensive, bidirectional crosstalk between tumour cells and the TME include CAFs, ECs, and immune cells. Tumours release factors such as PDGF and TGF-β, causing metabolic reprogramming in CAFs towards aerobic glycolysis, releasing energetic substrates such as lactate into the TME in a phenomenon known as ‘tumour-feeding.’ Meanwhile, tumour depletion of lactate, glutamine, and FAs in the TME lead to EC aberrant angiogenesis, which promotes proliferation and metastasis. VEGF is also released by tumours to promote EC proliferation. Tumour cells also induce metabolic changes to immune cells and cause immunosuppression. This is due to metabolic competition between immune cells and tumours for the same nutrients, producing an ‘exhausted’ T cell phenotype. Metabolic wastes, including lactate and kynurenine, are also released and impair T cell function, causing polarisation towards pro-tumorigenic T cell subtypes.

Figure 3

Effect of tumour metabolism on T cell function. (1) Altered cancer cell metabolism results in nutrient competition, depriving T cells of essential nutrients essential for robust anti-tumour activity, including glucose and key amino acids. Resultant exhausted T cell phenotype shows upregulation of inhibitory receptors including PD-1, CTLA-4, TIM-3, LAG-3, and TIGIT, impaired production and release of effector cytokines (IFNγ, IL-2, and TNF-α), as well as impaired degranulation. (2) Depletion of key nutrients and aberrant metabolite signalling promotes pro-tumourigenic T cell phenotypes. (3) Cancer cell metabolism produces lactate and other ‘waste’ metabolites that inhibit T cell function and promote T cell exhaustion.