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

  • Cell Metab. 2022 Sep 7;S1550-4131(22)00359-X. doi: 10.1016/j.cmet.2022.08.016.
Sheng Chen  1 ,  Wenyu Cui  2 ,  Zhexu Chi  3 ,  Qian Xiao  4 ,  Tianyi Hu  3 ,  Qizhen Ye  3 ,  Kaixiang Zhu  3 ,  Weiwei Yu  5 ,  Zhen Wang  3 ,  Chengxuan Yu  4 ,  Xiang Pan  4 ,  Siqi Dai  4 ,  Qi Yang  6 ,  Jiacheng Jin  3 ,  Jian Zhang  3 ,  Mobai Li  3 ,  Dehang Yang  3 ,  Qianzhou Yu  3 ,  Quanquan Wang  4 ,  Xiafei Yu  7 ,  Wei Yang  7 ,  Xue Zhang  8 ,  Junbin Qian  9 ,  Kefeng Ding  10 ,  Di Wang  11
Affiliations
  • 1. Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China.
  • 2. Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Eye Center, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 3. Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 4. Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China.
  • 5. Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 6. Department of Pathology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 7. Department of Biophysics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 8. Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China.
  • 9. Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Institute of Genetics, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China.
  • 10. Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Cancer Center, Zhejiang University, Hangzhou 310058, P.R. China. Electronic address: [email protected].
  • 11. Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, P.R. China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, P.R. China. Electronic address: [email protected].
PMID: 36103895 DOI: 10.1016/j.cmet.2022.08.016
Abstract

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.
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