Cancer cell lipid membranes and membrane-associated proteins in acidic tumor microenvironment

The acidic tumor microenvironment (TME) is a hallmark of solid tumors, characterized by an extracellular pH (pHe) significantly lower than that of healthy tissues [1, 17]. This acidity arises from the metabolic shift of cancer cells toward aerobic glycolysis (the Warburg effect) and poor vascular clearance of acidic byproducts like lactic acid and protons [9, 22]. The lipid membranes of cancer cells in this environment exhibit unique biophysical properties, such as altered fluidity and the exposure of specific lipids like phosphatidylserine [11, 13]. Furthermore, membrane-associated proteins including Carbonic Anhydrase IX (CAIX), V-ATPases, and monocarboxylate transporters (MCTs) are upregulated to maintain a neutral intracellular pH, facilitating tumor survival and invasion [17, 18]. Therapeutic strategies targeting these components include pH-low insertion peptides (pHLIPs), which selectively insert into the lipid bilayer at low pH to deliver cytotoxic or imaging payloads [5, 7, 10]. Inhibitors of pH-regulating proteins, such as CAIX and MCT1, are also being developed to disrupt the pH gradient and induce cancer cell death [17, 19]. This targeting approach offers a way to overcome tumor heterogeneity and improve the selectivity of cancer treatments [19, 20]. By exploiting the physical mechanism of membrane-associated folding, these therapies can target acidic tissues regardless of specific genetic mutations [7, 8]. However, challenges remain regarding off-target effects in naturally acidic organs like the stomach and kidneys [19]. Overall, targeting the acidic TME represents a promising frontier in precision oncology [1, 3].

Other names

Acidic tumor microenvironment (TME) membrane targetsTumor aciditypH-sensitive membrane targetsCancer cell membrane acidityAcidic TME-associated membrane components

pH-dependent membrane insertion and inhibition of membrane-associated pH regulatory proteins [5, 17]