Tumor Microenvironment Acidosis and Alkalization-Oriented Interventions in Advanced Solid Tumors: A Narrative Review and Science-Based Medicine Perspective on Long-Tail Survival

Median overall survival (OS) is a useful summary statistic in oncology, but it can obscure a clini-cally important and recurring phenomenon: a non-negligible fraction of patients with advanced (stage IV) solid tumors survive far beyond the median, forming a long tail on the survival curve. Accumulating mechanistic evidence indicates that tumor microenvironment (TME) acido-sis—driven by aerobic glycolysis, hypoxia, and proton-export systems (e.g., NHE1, monocarbox-ylate transporters, carbonic anhydrase IX, and V-ATPase)—promotes invasion, therapy resistance, and immune suppression. Buffering and other alkalization strategies can partially neutralize acidic TME in preclinical models and may enhance antitumor immunity, suggesting that modulating extracellular pH (pHe) is a plausible system-level lever. Science-based medicine (SBM) provides a complementary framework to evidence-based medicine (EBM) by integrating population-level evidence with causal mechanisms and longitudinal patient data, viewing cancer as a complex, non-equilibrium system with multiple attractor states. From this perspective, long-tail survival is not merely an outlier but may represent a qualitative state transition of the tumor–host system. We summarize key biology of TME acidosis, review alkalization-oriented interventions and their translational challenges, and discuss implications for trial design, including endpoints and analyses that capture delayed separation of survival curves and tail effects.