A novel cancer treatment strategy based on metabolic intervention and ionic stress: inducing a dual metabolic-ionic crisis in cancer cells through the coupling of MCT inhibition and a high-sodium environment

The Warburg effect in cancer cells leads to hyperactive glycolysis, producing large amounts of lactate. To maintain intracellular pH homeostasis, cancer cells heavily rely on monocarboxylate transporters MCT1 and MCT4 to co-transport lactate and protons out of the cell, thereby avoiding "acid death" caused by acidosis. This thesis proposes a novel synergistic therapeutic strategy: utilizing ketone bodies such as β-hydroxybutyrate as competitive substrates for MCTs to inhibit lactate efflux, while simultaneously constructing a high extracellular sodium environment. This dual intervention forces cancer cells to switch to relying on the sodium-hydrogen exchanger (NHE) for acid extrusion, resulting in massive influx of sodium ions (Na⁺). The intracellular Na⁺ overload, on one hand, directly threatens cell survival (risk of "sodium death"), and on the other hand, forces cancer cells to continuously activate the energy-consuming sodium-potassium pump (Na⁺/K⁺-ATPase) to expel excess Na⁺. This process massively hijacks the already limited ATP reserves, plunging cancer cells into a "metabolic dilemma": their ATP is heavily diverted to processes essential for survival maintenance (ionic homeostasis), severely weakening their bioenergetic and biosynthetic capacities for proliferation, invasion, and metastasis, thereby achieving the goal of suppressing tumor development or even inducing its demise.