pH gradient reversal refers to intracellular alkalization and extracellular acidification commonly seen in malignant tumors. To meet their high anabolic demand, cancer cells rewire their glucose metabolism from oxidative phosphorylation to lactate fermentation, which results in the excessive generation of protons. To avoid lethal cytosolic acidification, lactate-fermenting cancer cells activate multiple acid removal pathways leading to the acidification of the extracellular space. This acidification is often further intensified by the defective capacity of the disorganized tumor vasculature to dilute protons away from the cancer tissue. The cancer-specific proton equilibrium with highly alkaline cytosol and acidic extracellular space is emerging as a fundamental driving force for cancer growth. Here, we discuss how cancer cells establish and maintain reversed pH gradient, how pH gradient reversal fuels cancer progression, and how these mechanisms can be targeted in cancer therapy.

pH梯度逆转是指在恶性肿瘤中常见的细胞内碱化和细胞外酸化。为了满足其较高的合成代谢需求，癌细胞将其葡萄糖代谢从氧化磷酸化转变为乳酸发酵，这导致了质子的过量生成。为了避免致命的胞质酸化，发酵乳酸的癌细胞会激活多种除酸途径，导致细胞外空间发生酸化。紊乱的肿瘤脉管系统将质子从癌组织中稀释出来的能力不足，常常会进一步加剧这种酸化作用。具有高度碱性的细胞溶质和酸性的细胞外间隙的特定于癌症的质子平衡正在成为癌症生长的基本动力。这里，