Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1

Cell Metab. 2022 Nov 1;34(11):1843-1859.e11. doi: 10.1016/j.cmet.2022.08.016. Epub 2022 Sep 13.


The tumor microenvironment (TME) is a unique niche governed by constant crosstalk within and across all intratumoral cellular compartments. In particular, intratumoral high potassium (K+) has shown immune-suppressive potency on T cells. However, as a pan-cancer characteristic associated with local necrosis, the impact of this ionic disturbance on innate immunity is unknown. Here, we reveal that intratumoral high K+ suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). We identify the inwardly rectifying K+ channel Kir2.1 as a central modulator of TAM functional polarization in high K+ TME, and its conditional depletion repolarizes TAMs toward an anti-tumor state, sequentially boosting local anti-tumor immunity. Kir2.1 deficiency disturbs the electrochemically dependent glutamine uptake, engendering TAM metabolic reprogramming from oxidative phosphorylation toward glycolysis. Kir2.1 blockade attenuates both murine tumor- and patient-derived xenograft growth. Collectively, our findings reveal Kir2.1 as a determinant and potential therapeutic target for regaining the anti-tumor capacity of TAMs within ionic-imbalanced TME.

Keywords: Kir2.1; immunometabolism; potassium; tumor microenvironment; tumor-associated macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Mice
  • Neoplasms* / metabolism
  • Potassium / metabolism
  • Potassium Channels, Inwardly Rectifying* / metabolism
  • Tumor Microenvironment
  • Tumor-Associated Macrophages


  • Potassium Channels, Inwardly Rectifying
  • Potassium