1. Academic Validation
  2. 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: dingkefeng@zju.edu.cn.
  • 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: diwang@zju.edu.cn.
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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