Why Targeting Tumor Acidity Fails: Translational Barriers and Emerging Solutions.

Tumor acidity is a hallmark of the tumor microenvironment (TME) and has been widely regarded as a promising therapeutic target due to its ubiquity, functional relevance, and apparent selectivity for malignant tissues. Extensive preclinical studies have demonstrated that targeting tumor acidity-through inhibition of lactate production, blockade of proton transport, systemic buffering, and pH-responsive drug delivery-can suppress tumor growth, reduce metastasis, and enhance antitumor immunity. However, despite strong mechanistic rationale and consistent preclinical efficacy, these strategies have failed to achieve meaningful and durable clinical success. In this review, we examine the underlying reasons for this translational discrepancy. We highlight key mechanistic and systemic barriers, including spatial heterogeneity of tumor pH, temporal dynamics and adaptive evolution, metabolic plasticity, redundancy of pH-regulating systems, systemic physiological constraints, and drug delivery limitations in hypoxic and acidic regions. We further argue that tumor acidity is not a sufficient standalone driver of tumor progression but rather a feature of a complex and adaptive system shaped by metabolic and microenvironmental interactions. Finally, we discuss emerging strategies that may overcome these limitations, including combination therapies integrating metabolic targeting with immunotherapy, pH-responsive drug delivery systems, microenvironment reprogramming, and biomarker-guided patient stratification. Overall, current evidence suggests that future therapeutic approaches may benefit more from exploiting tumor acidity as a feature of the tumor microenvironment rather than attempting to directly neutralize it.