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Targeting the lactic acid metabolic pathway for antitumor therapy.

ABSTRACT: Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.

SUBMITTER: Li Z

PROVIDER: S-EPMC10682057 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Targeting the lactic acid metabolic pathway for antitumor therapy.

Li Zhi Z Cui Jiuwei J

Molecular therapy oncolytics 20231031

Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune ...[more]

PMID: 38033399

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Project description:Regulatory T (Treg) cells are vital for maintaining immune homeostasis and preventing autoimmunity, but represent a major barrier to robust cancer immunity as the tumor microenvironment (TME) actively recruits, activates, and promotes their differentiation1,2. Tumor cells have deregulated cellular metabolism leading to a metabolite-depleted, hypoxic, and acidic TME3. Highly glycolytic tumor infiltrating CD8 T cells are in direct competition with the tumor for glucose and oxygen which impairs their effector function4–6. In contrast, Treg cells maintain their high suppressive function within the TME7,8. Further, studies of in vitro induced and directly ex vivo Treg cells reveal a distinct metabolic profile compared to effector T cells9–11. Thus, we hypothesized that the altered metabolic landscape of the TME and the increased activity of intratumoral Treg cells are linked. Here we show Treg cells display heterogeneity in terms of their glucose metabolism and can engage an alternative metabolic pathway to maintain their high suppressive function and proliferation within the TME and other tissues. Tissue derived Treg cells (both at the steady state and under inflammatory conditions) show broad heterogeneity in their ability to take up glucose. However, glucose uptake correlates with poorer suppressive function and long-term functional stability, and culture of Treg cells in high glucose conditions decreased suppressive function. Treg cells under low glucose conditions upregulate genes associated with the uptake and metabolism of the glycolytic end-product lactic acid. Treg cells withstand high lactate conditions, and lactate treatment prevents the destabilizing effects of high glucose culture. Treg cells utilize lactate within the TCA cycle and generate phosphoenolpyruvate (PEP), a critical intermediate that can fuel intratumoral Treg cell proliferation in vivo. Using mice with a Treg cell-restricted deletion of lactate transporter Slc16a1 (MCT1) we show MCT1 is dispensable for peripheral Treg cell function but required intratumorally, resulting in slowed tumor growth and prolonged survival. These data support a model in which Treg cells are metabolically flexible such that they can utilize ‘alternative’ metabolites present in the TME to maintain their suppressive identity. Further, our studies support the notion that tumors avoid immune destruction not only by depriving effector T cells of essential nutrients, but also by metabolically supporting regulatory T cells.

Dataset Information

Targeting the lactic acid metabolic pathway for antitumor therapy.

Publications

Targeting the lactic acid metabolic pathway for antitumor therapy.

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