Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy

Abstract

Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.

Keywords: T cell metabolism; immune checkpoint; immune checkpoints inhibitor; metabolic reprogramming; tumor microenvironment.

Figure 1

Strategies for targeting CD8+ T cell metabolism in combination with ICIs. Using small-molecule drugs or gene interference technology to target relevant elements in the metabolic pathways in the cytoplasm (A) and mitochondria (B) of CD8+ T cells, or targeting transcription factors that regulate metabolism (B), can improve the efficacy of ICI therapy and exert a greater antitumor effect.