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

• Published in: Cell metabolism 2022-11, Vol.34 (11), p.1843-1859.e11
• Main Authors: Chen, Sheng, Cui, Wenyu, Chi, Zhexu, Xiao, Qian, Hu, Tianyi, Ye, Qizhen, Zhu, Kaixiang, Yu, Weiwei, Wang, Zhen, Yu, Chengxuan, Pan, Xiang, Dai, Siqi, Yang, Qi, Jin, Jiacheng, Zhang, Jian, Li, Mobai, Yang, Dehang, Yu, Qianzhou, Wang, Quanquan, Yu, Xiafei, Yang, Wei, Zhang, Xue, Qian, Junbin, Ding, Kefeng, Wang, Di
• Format: Article
• Language: English
• Subjects: Animals; Humans; immunometabolism; Kir2.1; Mice; Neoplasms - metabolism; potassium; Potassium - metabolism; Potassium Channels, Inwardly Rectifying - metabolism; Tumor Microenvironment; tumor-associated macrophage; Tumor-Associated Macrophages
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2022.08.016

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. [Display omitted] •Intratumoral high potassium shapes TAM polarization•Kir2.1 is essential for TAM polarization within high K+ TME•Kir2.1 deficiency disturbs electrochemically dependent GLN uptake•Pharmacological blockade of Kir2.1 inhibits both murine and human tumor growth Chen et al. demonstrate that intratumoral high potassium inhibits the anti-tumor capacity of TAMs via Kir2.1, which supports macrophage electrochemically dependent glutamine uptake. Genetic depletion or pharmacological blockade of Kir2.1 repolarizes TAMs toward the anti-tumor state and attenuates both transplanted murine tumor and patient-derived xenograft growth.