Tumor extracellular acidity

Tumor extracellular acidity refers to the abnormally low pH (typically pH 6.5–6.9) in the tumor microenvironment, compared to normal tissue (pH ~7.4), primarily caused by increased glycolytic metabolism (Warburg effect), poor perfusion, and upregulation of acid-transporting proteins such as carbonic anhydrase IX. This acidic microenvironment is implicated in a range of biological processes that drive cancer progression, including induction of invasive and metastatic phenotypes, resistance to some therapies, suppression of immune cell function, and modulation of gene expression. It is considered a **hallmark of cancer**, but it is not a conventional single molecular drug target (such as a receptor or enzyme). Instead, it represents a therapeutic vulnerability: several drugs and experimental agents aim to exploit or neutralize tumor acidity, for example by using acid-activated peptides, proton pump inhibitors, or systemic buffers. Targeting tumor extracellular acidity is challenging due to the risk of disrupting normal pH homeostasis in healthy tissues. Current research involves both exploiting this environment for tumor-specific drug delivery and directly neutralizing acidity to impair tumor growth or enhance immune response[1][2][3][4][5][6].

Other names

Acidic tumor microenvironmentTumor microenvironment acidityTumor pHe (tumor extracellular pH)Acidic TME

Inhibition of carbonic anhydrase to reduce acid formation (e.g., acetazolamide, AZD7986); Buffering of extracellular pH to neutralize acidity (e.g., sodium bicarbonate); Inhibition of proton pumps to decrease extracellular acidification (e.g., omeprazole, esomeprazole); Inhibition of V-ATPase to block proton extrusion (e.g., bafilomycin A1); Modulation of tumor metabolism to reduce lactic acid production (e.g., DCA, bromopyruvate, CPI-613); Acid-targeted delivery (e.g., pH low insertion peptide [pHLIP], 5-aminolevulinic acid with photodynamic therapy)