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Metabolic plasticity and immune function

Cellular metabolism is orchestrated by more than 2000 metabolic enzymes organized into pathways that are specialized for processing and producing distinct metabolites. Multiple metabolites are shared by different pathways, serving as nodes in a complex metabolic network with many redundant/compensatory elements. As cellular metabolism is foundational to all cellular activities, targeting metabolic enzymes represents an effective approach to suppress pathogenic cell behavior and recently has received increasing attention in the fields of immunology and cancer. However, many of the metabolic pathways are essentially required by the majority of , if not all, the cells in the body (e.g. glycolysis, mitochondrial respiration etc.). Therefore, translating metabolic targeting to the clinic has been greatly limited due to broad toxicity, despite its successful inhibition of pathogenic cells. Our previous work has justified a strategy to circumvent these limitations by targeting redundant/compensatory metabolic enzymes, the products of which can be generated by other enzymes or pathways. While inactivation of non-redundant 

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metabolic enzymes, such as Gapdh, could lead to global toxicity, removal of redundant enzymes will allow for compensation (accompanied with metabolic network reorganization) and thus be better tolerated. Importantly, the compensatory pathway may be inactive in certain cell types or environmental settings, making them particularly vulnerable to the manipulation, achieving specificity in metabolic targeting. Moreover, the enhanced compensatory activity in the spared cells may at the same time promote cell function that is beneficial to disease treatment, further reinforcing the therapeutic efficacy. Identifying such metabolic enzymes will certainly increase the clinic potential of metabolic targeting approach. To date it remains unknown which metabolic components are redundant/compensatory as well as how metabolic plasticity is regulated by environmental factors or cell identity. The lab has been equipped with state-of-the-art technologies (in vivo CRISPR screen, metabolic tracing and flux analysis), aiming to address several critical questions with T cells in autoimmune and cancer mouse models - (1) which metabolic enzymes have redundant/compensatory elements, (2) how cells reorganize the metabolic network for tolerating removal of such enzymes, (3) how microenvironmental factors or cell identities affect such compensation, and (4) what is the functional impact of the metabolic network reorganization for cells of different identities or in different tissue microenvironments. These studies will generate deeper insights into how metabolism, as a plastic network, regulates tissue- and cell-specific functions, which would lead to novel approaches for autoimmune and cancer treatment.

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