Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1
Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1
复制标题
肿瘤相关巨噬细胞由肿瘤内高钾通过 Kir2.1 塑造。
DOI：
10.1016/j.cmet.2022.08.016
复制
发表时间：
2022-11-01
期刊：
影响因子：
29
通讯作者：
Wang, Di
中科院分区：
文献类型：
--
作者：
Chen, Sheng;Cui, Wenyu;Wang, Di
肿瘤微环境(TME)是一个独特的利基环境，由肿瘤内和肿瘤内所有细胞间持续的串扰控制。尤其是肿瘤内的高钾(K+)对T细胞表现出免疫抑制作用。然而，作为一种与局部坏死相关的泛癌特征，这种离子紊乱对天然免疫的影响尚不清楚。在这里，我们揭示了肿瘤内高K+抑制肿瘤相关巨噬细胞(TAMs)的抗肿瘤能力。我们确认内向整流性K+通道Kir2.1是高K+TME时功能极化的中枢调节器，它的条件性耗竭使TAMs重新极化为抗肿瘤状态，从而增强局部抗肿瘤免疫。Kir2.1缺乏干扰了电化学依赖的谷氨酰胺摄取，导致代谢重新编程，从氧化磷酸化转向糖酵解。Kir2.1阻断可减弱小鼠肿瘤和患者来源的异种移植生长。总而言之，我们的发现显示Kir2.1是在离子平衡的TME中恢复TAMS抗肿瘤能力的一个决定性的和潜在的治疗靶点。
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 -sup-pressive 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 deter-minant and potential therapeutic target for regaining the anti-tumor capacity of TAMs within ionic-imbal-anced TME.