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Fueling the Revolution: Targeting Metabolism to Enhance Immunotherapy.

ABSTRACT: The success of immune-checkpoint blockade and chimeric antigen receptor (CAR) T cell therapies has established the remarkable capacity of the immune system to fight cancer. Over the past several years, it has become clear that immune cell responses to cancer are critically dependent upon metabolic programs that are specific to both immune cell type and function. Metabolic features of cancer cells and the tumor microenvironment impose constraints on immune cell metabolism that can favor immunosuppressive phenotypes and block antitumor responses. Advances in both preclinical and clinical studies have demonstrated that metabolic interventions can dramatically enhance the efficacy of immune-based therapies for cancer. As such, understanding the metabolic requirements of immune cells in the tumor microenvironment, as well as the limitations imposed therein, can have significant benefits for informing both current practice and future research in cancer immunotherapy.

SUBMITTER: Leone RD

PROVIDER: S-EPMC8240594 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cellular metabolism is not only essential for tumor cells to sustain their rapid growth and proliferation, but also crucial to maintain T cell fitness and robust immunity. Dysregulated metabolism has been recognized as a hallmark of cancer, which provides survival advantages for tumor cells under stress conditions. Also, emerging evidence suggests that metabolic reprogramming impacts the activation, differentiation, function, and exhaustion of T cells. Normal stimulation of resting T cells promotes the conversion of catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and subsequently back to oxidative metabolism in memory T cells. These metabolic transitions profoundly affect the trajectories of T-cell differentiation and fate. However, these metabolic events of T cells could be dysregulated by their interplays with tumor or the tumor microenvironment (TME). Importantly, metabolic competition in the tumor ecosystem is a new mechanism resulting in strong suppression of effector T cells. It is appreciated that targeting metabolic reprogramming is a promising way to disrupt the hypermetabolic state of tumor cells and enhance the capacity of immune cells to obtain nutrients. Furthermore, immunotherapies, such as immune checkpoint inhibitor (ICI), adoptive cell therapy (ACT), and oncolytic virus (OV) therapy, have significantly refashioned the clinical management of solid tumors, they are not sufficiently effective for all patients. Understanding how immunotherapy affects T cell metabolism provides a bright avenue to better modulate T cell anti-tumor response. In this review, we provide an overview of the cellular metabolism of tumor and T cells, provide evidence on their dynamic interaction, highlight how metabolic reprogramming of tumor and T cells regulate the anti-tumor responses, describe T cell metabolic patterns in the context of ICI, ACT, and OV, and propose hypothetical combination strategies to favor potent T cell functionality.

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Fueling the Revolution: Targeting Metabolism to Enhance Immunotherapy.

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