Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells

Cell Metab. 2022 Aug 2;34(8):1137-1150.e6. doi: 10.1016/j.cmet.2022.06.008. Epub 2022 Jul 11.


The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.

Keywords: T cells; cancer metabolism; lactate; pyruvate; succinate; tumor immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD8-Positive T-Lymphocytes / metabolism
  • Humans
  • Immunity
  • Lactic Acid
  • Neoplasms*
  • Pyruvate Carboxylase / metabolism
  • Pyruvic Acid* / metabolism
  • Pyruvic Acid* / pharmacology
  • Succinic Acid
  • Tumor Microenvironment


  • Lactic Acid
  • Pyruvic Acid
  • Succinic Acid
  • Pyruvate Carboxylase