MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma

Cancer Cell. 2023 Jul 10;41(7):1363-1380.e7. doi: 10.1016/j.ccell.2023.05.015. Epub 2023 Jun 15.


Inactivating STK11/LKB1 mutations are genomic drivers of primary resistance to immunotherapy in KRAS-mutated lung adenocarcinoma (LUAD), although the underlying mechanisms remain unelucidated. We find that LKB1 loss results in enhanced lactate production and secretion via the MCT4 transporter. Single-cell RNA profiling of murine models indicates that LKB1-deficient tumors have increased M2 macrophage polarization and hypofunctional T cells, effects that could be recapitulated by the addition of exogenous lactate and abrogated by MCT4 knockdown or therapeutic blockade of the lactate receptor GPR81 expressed on immune cells. Furthermore, MCT4 knockout reverses the resistance to PD-1 blockade induced by LKB1 loss in syngeneic murine models. Finally, tumors from STK11/LKB1 mutant LUAD patients demonstrate a similar phenotype of enhanced M2-macrophages polarization and hypofunctional T cells. These data provide evidence that lactate suppresses antitumor immunity and therapeutic targeting of this pathway is a promising strategy to reversing immunotherapy resistance in STK11/LKB1 mutant LUAD.

Keywords: LKB1; MCT4; PD-1; T cell activation; immunotherapy resistance; lactate; lung adenocarcinoma; macrophage polarization; metabolism.

Publication types

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

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Adenocarcinoma of Lung* / metabolism
  • Adenocarcinoma of Lung* / therapy
  • Animals
  • Lactates / metabolism
  • Lactates / pharmacology
  • Lactates / therapeutic use
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / therapy
  • Macrophages
  • Mice
  • Mutation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism


  • Lactates
  • Protein Serine-Threonine Kinases
  • Slc16a4 protein, mouse