Cell membrane lipid bilayer in acidic tumor microenvironment (TME lipid bilayer)

The cell membrane lipid bilayer in the acidic tumor microenvironment (TME) serves as a distinct physical and chemical target for selective drug delivery. Due to the Warburg effect, cancer cells undergo high rates of aerobic glycolysis, resulting in the secretion of lactic acid and a subsequent drop in extracellular pH to approximately 6.0–6.8 (Gatenby & Gillies, 2004). This localized acidity distinguishes the tumor surface from healthy tissues, which maintain a physiological pH of 7.4. Specialized molecules, such as pH-Low Insertion Peptides (pHLIPs), exploit this gradient by undergoing a conformational change from an unstructured coil to an alpha-helix that inserts directly into the lipid bilayer under acidic conditions (Reshetnyak et al., 2006). This mechanism enables the targeted translocation of membrane-impermeable payloads, including cytotoxins, imaging agents, and oligonucleotides, specifically into malignant cells (Andreev et al., 2014). By targeting the universal metabolic signature of acidity rather than specific protein receptors, this approach can potentially overcome tumor heterogeneity and resistance. However, therapeutic development must account for potential off-target effects in other acidic physiological compartments, such as the kidneys or areas of acute inflammation.

Other names

Acidic tumor cell membraneTumor microenvironment lipid bilayerAcid-sensitive cell membranepHLIP target membrane

pH-dependent conformational change and membrane insertion of therapeutic peptides or delivery vehicles