Immunometabolites and cancer: the role of 2-hydroxyglutarate, succinate, fumarate and itaconate in tumour development and anti-tumour immunity

The field of immunometabolism has expanded substantially in recent years, with specific metabolic change becoming a key feature that defines the phenotype of immune cells. In cancer however, metabolic change has been investigated for much longer, and the exploration of oncometabolites as immunometabolites is increasingly being explored. 2-hydroxyglutarate was one of the first oncometabolites to be implicated in tumourigenesis but it also has immunomodulatory effects, with the D enantiomer suppressing anti-tumour immunity via various processes including inhibition of CD8⁺T cells. Fumarate also acts as an oncometabolite, affecting DNA methylation and DNA repair, but again also having immunomodulatory effects via inhibition of T and B cells, whilst also promoting Type I interferon production in macrophages. Succinate can act as an oncometabolite but also in immunomodulation. It has been shown to have pro-tumour effects, acting via HIF-1α and epigenetic modification and regulating tumour-associated macrophages (TAMs). Succinate can also promote T cell exhaustion whilst expanding cancer-associated fibroblasts. Finally, itaconate has been shown to have pro-tumour effects, by either supporting tumour cell survival or by suppressing anti-tumour immunity. TAMs and myeloid-derived suppressor cells are a source of itaconate, which can inhibit CD8⁺T cell responses and suppress tumour antigen presentation by dendritic cells. Emerging evidence indicates that the targeting of these metabolites holds promise for limiting tumour growth but in addition boosting anti-tumour immunity.