Acidic tumor cell plasma membrane (pHe)

The acidic tumor cell plasma membrane is a physiological hallmark of solid tumors, primarily arising from the Warburg effect, where cancer cells exhibit high rates of glycolysis and lactic acid fermentation even in the presence of oxygen (Reshetnyak et al., 2006; Andreev et al., 2014). This metabolic reprogramming leads to the active extrusion of protons and lactate into the extracellular space, resulting in a significantly lower extracellular pH (pHe 6.2–6.9) compared to normal tissues (pHe 7.4) (He et al., 2013; Kato et al., 2013). This acidic microenvironment facilitates tumor progression by promoting extracellular matrix degradation, increasing invasiveness and metastasis, and suppressing anti-tumor immune responses (Damaghi et al., 2013; Kato et al., 2013). Furthermore, the pH gradient across the plasma membrane creates a physical barrier known as "ion trapping," which limits the uptake of weakly basic chemotherapeutic drugs (Kato et al., 2013). Therapeutic strategies exploit this acidity as a target for selective delivery, utilizing pH-responsive agents such as pH-Low Insertion Peptides (pHLIP) that undergo a conformational change to insert into the membrane at low pH, or pH-sensitive nanoparticles that release their cargo specifically in the acidic tumor milieu (Andreev et al., 2014; Reshetnyak et al., 2006).

Other names

Tumor extracellular acidityAcidic tumor microenvironmentLow extracellular pHTumor acidosisTumor cell surface acidity

Drugs targeting the acidic tumor cell plasma membrane typically utilize the low extracellular pH to trigger site-specific actions. This includes the pH-dependent insertion of peptides (e.g., pHLIP) into the lipid bilayer, the release of therapeutic payloads from pH-sensitive nanoparticles or liposomes, and the neutralization of the acidic microenvironment using buffering agents to enhance immune cell activity and drug penetration.