Abstract
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.
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Acknowledgements
S.J.M. is supported by a Graduate Award from the University of Victoria and G.A.C. is supported by a Vanier Canada Graduate Scholarship. This manuscript was supported by grants from the Canadian Institutes of Health Research (PJT407274; to J.J.L.), the Terry Fox Research Institute New Frontiers Program Project (to J.J.L.) and a US Department of Defence Ovarian Cancer Research Program Teal Expansion Award (OC210019; to J.J.L.). The authors apologize to researchers in the field whose work has been inadvertently overlooked or could not be cited due to space restrictions. The laboratory of J.J.L. is situated on the traditional territory of the lək̓ʷəŋən People, specifically the Songhees and Esquimalt First Nations. We acknowledge and respect our traditional hosts and thank them for allowing us to conduct research while on their lands.
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J.J.L. and S.M. conceived the idea. J.J.L. and S.M. designed the scope of the article and conducted the literature review. S.M. compiled the reference list, drafted the initial manuscript and created the figures and tables. All authors contributed to reviewing, editing and revising the article, figures and tables for intellectual content and clarity.
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McPhedran, S.J., Carleton, G.A. & Lum, J.J. Metabolic engineering for optimized CAR-T cell therapy. Nat Metab 6, 396–408 (2024). https://doi.org/10.1038/s42255-024-00976-2
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DOI: https://doi.org/10.1038/s42255-024-00976-2
