Metabolic engineering for optimized CAR-T cell therapy.

The broad effectiveness of T cell-based therapy for treating solid tumour cancers remains limited. This is partly due to the growing appreciation that immune cells must inhabit and traverse a metabolically demanding tumour environment. Accordingly, recent efforts have centred on using genome-editing technologies to augment T cell-mediated cytotoxicity by manipulating specific metabolic genes. However, solid tumours exhibit numerous characteristics restricting immune cell-mediated cytotoxicity, implying a need for metabolic engineering at the pathway level rather than single gene targets. This emerging concept has yet to be put into clinical practice as many questions concerning the complex interplay between metabolic networks and T cell function remain unsolved. This Perspective will highlight key foundational studies that examine the relevant metabolic pathways required for effective T cell cytotoxicity and persistence in the human tumour microenvironment, feasible strategies for metabolic engineering to increase the efficiency of chimeric antigen receptor T cell-based approaches, and the challenges lying ahead for clinical implementation.

Assessing the Immune Regulatory Role of Metabolites In Vitro.

One method of immune evasion that cancer cells employ is the secretion of immune regulatory metabolites into the tumor microenvironment (TME). These metabolites can promote immunosuppressive cell subsets, while inhibiting key tumor-killing subsets, such as T cells. Thus, the identification of these metabolites may help develop methods for improving cell-based therapy. However, after identifying a potential immune regulatory metabolite, it is crucial to assess the impacts of the metabolite on T cell immunobiology. In this chapter, we describe an in vitro method of testing and analyzing the influence of a specific metabolite on T cell proliferation and function.

Ubiquitinating the way to T cell metabolism.

In this issue, Harris et al. (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202203095) show that phosphofructokinase is a substrate for ubiquitination by Fbxo7, a key protein in the ubiquitination pathway. Their findings point to a new interplay between metabolic enzyme degradation in the regulation of T cells.