Pyruvate Metabolism Enables Antitumor Succinate Signaling in CD8⁺ T Cells

In order to design immunotherapeutic strategies that elicit durable responses in patients, a comprehensive understanding of the various ways in which the tumor microenvironment (TME) can suppress effective antitumor immunity is essential. Given that CD8⁺ T-cell activation requires a shift in metabolism, Elia and colleagues explored whether the unique profile of metabolic availability within the TME influences CD8⁺ T-cell metabolic reprogramming and subsequent cytotoxicity. To mimic the TME metabolic niche, conditioned media (CM) were collected after 24 hours of coculture of activated murine CD8⁺ T cells with cognate antigen–expressing tumor cells. Coculture of CD8⁺ T cells and tumor cells in CM significantly impaired T-cell killing, while metabolic profiling analysis revealed that CD8⁺ T cells cocultured in CM exhibited increased entry of carbons into the tricarboxylic acid (TCA) cycle, primarily through the activity of pyruvate dehydrogenase (PDH) rather than pyruvate carboxylase (PC). Compared with baseline media, CM harbored significantly higher levels of tumor-derived lactate, and high lactate media were sufficient to hinder PC activity and CD8⁺ T-cell killing, suggesting that lactate secretion by tumor cells impairs CD8⁺ T-cell metabolism and function. Notably, since pyruvate can enter the TCA cycle through either PC or PDH, pharmacologic inhibition of PDH increased pyruvate availability for PC, rescuing both PC activity and effector function of CD8⁺ T cells. Evidence also supports that PC activity promotes cytotoxicity by replenishing TCA cycle intermediates, with further studies revealing that anaplerotic PC function was important to enable CD8⁺ T cells in coculture to actively secrete succinate, thereby promoting autocrine signaling through the succinate receptor SUCNR1 to enhance CD8⁺ T-cell killing and IFNγ production. Moreover, use of genetic or pharmacologic inhibition of PDH in a syngeneic murine tumor model led to reduced tumor growth through CD8⁺ T cell–dependent tumor control and synergized with anti–PD-1 immunotherapy. In summary, this work reveals how the metabolic niche of the TME alters pyruvate metabolism to attenuate CD8⁺ T-cell function.

Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8⁺ T cells. Cell Metab 2022;34:1137–50.e6.

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