Researchers have found a novel therapeutic target to enhance the effects of cancer immunotherapy. A study published today in Science Immunology reveals how a metabolite known as citraconate can reduce T cell exhaustion and enhance the ability of these immune cells to live longer, multiply, and effectively fight tumors.
Despite the widespread success of checkpoint inhibitor immunotherapies, a substantial proportion of patients still do not respond to these treatments. One contributing factor is metabolic dysregulation within the tumor microenvironment (TME), which compromises the antitumor activity of tumor-infiltrating T cells and limits their proliferation, reducing the efficacy of immunotherapy.
“Emerging evidence highlights the TME as a formidable metabolic barrier to immune cell function, attributable, in part, to the accumulation of immunosuppressive metabolites, which collectively promote T cell exhaustion and resistance to immunotherapy,” writes Lianjun Zhang, PhD, professor at the Suzhou Institute of Systems Medicine and senior author of the study. “Although tumor-derived metabolites are increasingly recognized as key modulators of T cell dysfunction and antitumor immunity, the critical metabolic circuits and specific metabolites that shape and sustain T cell phenotypes remain incompletely characterized.”
Citraconate is known to have antioxidative and antiviral properties, as well as being involved in T cell exhaustion. However, the exact signaling pathways it activates and immunological functions it plays in the context of cancer still remain poorly understood.
Zhang’s team uncovered a previously unreported role for this metabolite in antitumor immunity, by reducing T cell exhaustion and preserving their ability to replicate. In tumor tissue samples from patients, the researchers found that citraconate was depleted within exhausted T cells. In cultured human cells and mouse models, supplementation with citraconate increased the activation of tumor-infiltrating T cells, promoted their division, and reduced exhaustion, boosting their antitumor activity.
Further examination revealed that citraconate triggers these effects by increasing intracellular levels of cAMP, which in turn represses the ALOX5 enzyme involved in the oxidation of fatty acids such as arachidonic acid. This signaling cascade reduces the vulnerability of T cells to ferroptosis, a form of cell death driven by the accumulation of oxidized lipids on the cell membrane.
Genetic and pharmacologic inhibition of ALOX5 enhanced antitumor immunity mediated by T cells, confirming these findings. In mouse models of cancer, supplementation with citraconate was shown to boost the effects of immune checkpoint therapy
Taken together, these findings unveil a critical metabolic checkpoint regulating the performance of tumor-infiltrating T cells, presenting a clinically actionable target to enhance the efficacy of immune checkpoint inhibitors. Going forward, the team plans to dive deeper into the signaling pathways that citraconate employs to modulate T cell activity, its role in metabolic regulation, and the potential contributions of epigenetics to the whole process.
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