Abstract
Breast cancer is the most common malignancy among women and a leading cause of cancer-related mortality worldwide.A critical but often underappreciated hallmark of this disease is dysregulated acid-base homeostasis within the tumor microenvironment (TME).Driven by the Warburg effect, cancer cells preferentially utilize aerobic glycolysis, producing excessive lactate and protons.This results in extracellular acidification while maintaining a neutral-to-alkaline intracellular pH, a state that promotes proliferation, invasion, immune evasion, and resistance to therapy.Central to pH regulation are transporters and enzymes such as monocarboxylate transporters (MCT1/4), Na⁺/H⁺ exchanger (NHE1), vacuolar H⁺-ATPases, and carbonic anhydrases, which coordinate proton efflux and buffering.Therapeutic strategies targeting these pathways include hexose derivatives (e.g., 2deoxy-D-glucose, D-mannose) that inhibit glycolytic flux, and citrate-based agents that buffer acidity and restore metabolic feedback inhibition.Additional approaches encompass lactate transport inhibition, bicarbonate therapy, and pH-responsive drug delivery systems.Preclinical evidence supports the efficacy of these interventions, and early clinical exploration suggests translational potential, particularly in aggressive subtypes such as triple-negative breast cancer.By disrupting the pH balance that supports tumor growth and survival, these strategies offer promising avenues for improved outcomes.This review provides a comprehensive overview of the molecular mechanisms and therapeutic opportunities for targeting acid-base regulation in breast cancer.