2. Academic Validation
  3. Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1

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

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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