Tumor microenvironment metabolites directing T cell differentiation and function

Metabolic dysfunction is a key hallmark of cancer, resulting in the accumulation of metabolites in the tumor microenvironment (TME), affecting both cancer cells and immune components. Abnormal production of metabolites in the TME is associated with negative clinical outcomes and disease progression of cancer patients. TME metabolites derived from glucose and lipid metabolism can direct the differentiation, function, and fate of tumor-infiltrating T cells, thereby affecting antitumor immunity and immunotherapy. Reprogramming of tumor metabolism in the TME, especially targeting key metabolites, has emerged as a novel and promising strategy for the treatment of certain tumors. Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions. Metabolic reprogramming of cancer cells creates a unique tumor microenvironment (TME) characterized by the limited availability of nutrients, which subsequently affects the metabolism, differentiation, and function of tumor-infiltrating T lymphocytes (TILs). TILs can also be inhibited by tumor-derived metabolic waste products and low oxygen. Therefore, a thorough understanding of how such unique metabolites influence mammalian T cell differentiation and function can inform novel anticancer therapeutic approaches. Here, we highlight the importance of these metabolites in modulating various T cell subsets within the TME, dissecting how these changes might alter clinical outcomes. We explore potential TME metabolic determinants that might constitute candidate targets for cancer immunotherapies, ideally leading to future strategies for reprogramming tumor metabolism to potentiate anticancer T cell functions. apolipoprotein E protein is a major cholesterol carrier for lipid transport in lipid metabolism, neurobiology, and neurodegenerative diseases. Deficient mice are used, for example, in atherosclerosis models. process mediated by lysosomal acid lipase, hydrolyzing TAG, DAG, and CE to generate free FA and cholesterol in lysosomes. subset of memory CD8+ T cells with high expression of CD62L and CCR7; have a centralized location within secondary lymphoid organs and superior proliferative abilities for handling systemic infections. expresses an αβ T cell receptor; present in peripheral blood, lymph nodes, and tissues; contains two major subsets, CD4+ Th cells and CD8+ cytotoxic cells, based on the respective expression of coreceptor CD4 or CD8. subset of memory CD8+ T cells with low expression of CD62L and CCR7; have cytotoxic ability and localize to inflamed tissues to provide protection against infection. protective stress response of cells; occurs when the capacity of the ER to fold proteins becomes saturated. type of programmed cell death; accompanied by a great amount of iron and lipid peroxidation during cell death. member of the forkhead transcription factor family that mainly controls Treg differentiation. histone H3 acetylation at the lysine 9 residue (H3K9Ac) and lysine 27 residue (H3K27Ac) are histone markers associated with active transcription. special cell–cell communication between an antigen-presenting cell or target cell and, for example, a lymphocyte, with subsequent cell activation. organelles composed of a neutral lipid core consisting mainly of triacylglycerols and cholesteryl esters surrounded by a phospholipid monolayer. lipid domains composed of sphingolipids and cholesterol in the outer exoplasmic leaflet; for modulating the membrane distribution of receptor and signaling molecules facilitating the assembly of active signaling platforms. process in which special organelles containing a series of proteins are secreted from cells and mediate target cell destruction after activation of CTLs and NK cells. T cells expressing transgenic TCR specific for the epitope of pmel-17 corresponding to B16 melanoma antigen gp100. long-lived subset of CD8+ T cells that are antigen specific and can elicit strong immune responses when encountering the same antigen. contain transgenic inserts for mouse Tcra-V2 and Tcrb-V5 genes; T cells from these mice recognize ovalbumin residues 257–264 in the context of H2Kb for studying the role of peptides in positive selection and the response of CD8+ T cells to antigens. panel of nuclear receptor proteins that function as transcription factors regulating gene expression for cell differentiation, development, metabolism. one subpopulation of CD4+ T cells with a suppression function to regulate and maintain immune homeostasis. retinoic acid-receptor related orphan receptor C, encodes protein RORγt, an important nuclear receptor regulating Th17 cell development. subset of CD8+ cytotoxic T cells that produce IL-9. T helper type 1 cells; one of the subsets of CD4+ T cells and involved in cell-mediated immune responses. subset of CD4+ T cells, secreting IL-4, IL-5, IL-10, and IL-13; involved in humoral or antibody-mediated immune responses. subset of CD4+ T cells characterized by IL-17 production; differentiation is regulated by transcription factors RORγt and RORα. They play important roles in autoimmune disorders and inflammation. memory lymphocyte population that resides in nonlymphoid tissues, such as the mucosal tissues and skin. subpopulations of cytotoxic CD8+ T cells that can produce IFN-γ to perform effector immune responses.