The high metabolic demand of cancer cells leads to an accumulation of H⁺ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H⁺ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H⁺ ions. Another major source of H⁺ ions results from hydration of CO₂ produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H⁺-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.

中文翻译：

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肿瘤酸中毒：从乘客到驾驶员座位

癌细胞的高代谢需求导致肿瘤微环境中H ⁺离子的积累。杂乱无章的肿瘤脉管系统阻止了释放到细胞外介质中的H ⁺离子的有效清除，但也促进了与糖酵解代谢相关的肿瘤低氧区域的发展。在缺氧条件下，糖酵解的最终平衡（包括生成的ATP的分解）是乳酸的产生和化学计量的H ⁺离子。H ⁺离子的另一个主要来源是CO _2的水合作用产生于氧化性更高的肿瘤区域。所有这些事件在肿瘤中发生率很高，以满足生物能和生物合成的需要。这篇综述总结了目前对H ⁺产生的代谢过程如何根据距血管的距离进行分离的理解，以及反过来环境酸中毒如何影响肿瘤代谢，减少糖酵解同时促进线粒体活性的认识。该评论还提出了新的见解，通过刺激自噬和免疫抑制来支持酸中毒参与癌症进展。最后，将讨论旨在阻止pH调节系统或利用酸中毒的不同治疗方法的最新进展。